
==== Front
Signal Transduct Target Ther
Signal Transduct Target Ther
Signal Transduction and Targeted Therapy
2095-9907
2059-3635
Nature Publishing Group UK London

38148355
1675
10.1038/s41392-023-01675-2
Review Article
Mpox (formerly monkeypox): pathogenesis, prevention and treatment
Lu Junjie 1
Xing Hui 1
Wang Chunhua 1
Tang Mengjun 1
Wu Changcheng 2
Ye Fan 1
Yin Lijuan 3
Yang Yang young@mail.sustech.edu.cn

4
http://orcid.org/0000-0002-5963-1136
Tan Wenjie tanwj@ivdc.chinacdc.cn

2
Shen Liang shenliang.0829@163.com

1
1 https://ror.org/02dx2xm20 grid.452911.a 0000 0004 1799 0637 Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei Province Xiangyang, 441021 China
2 grid.198530.6 0000 0000 8803 2373 NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206 China
3 https://ror.org/018rbtf37 grid.413109.e 0000 0000 9735 6249 College of Biotechnology, Tianjin University of Science & Technology, Tianjin, 300457 China
4 https://ror.org/04xfsbk97 grid.410741.7 Shenzhen Key Laboratory of Pathogen and Immunity, National Clinical Research Center for infectious disease, State Key Discipline of Infectious Disease, Shenzhen Third People’s Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, 518112 China
27 12 2023
27 12 2023
2023
8 45825 7 2023
14 9 2023
21 9 2023
© The Author(s) 2023
2023
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
In 2022, a global outbreak of Mpox (formerly monkeypox) occurred in various countries across Europe and America and rapidly spread to more than 100 countries and regions. The World Health Organization declared the outbreak to be a public health emergency of international concern due to the rapid spread of the Mpox virus. Consequently, nations intensified their efforts to explore treatment strategies aimed at combating the infection and its dissemination. Nevertheless, the available therapeutic options for Mpox virus infection remain limited. So far, only a few numbers of antiviral compounds have been approved by regulatory authorities. Given the high mutability of the Mpox virus, certain mutant strains have shown resistance to existing pharmaceutical interventions. This highlights the urgent need to develop novel antiviral drugs that can combat both drug resistance and the potential threat of bioterrorism. Currently, there is a lack of comprehensive literature on the pathophysiology and treatment of Mpox. To address this issue, we conducted a review covering the physiological and pathological processes of Mpox infection, summarizing the latest progress of anti-Mpox drugs. Our analysis encompasses approved drugs currently employed in clinical settings, as well as newly identified small-molecule compounds and antibody drugs displaying potential antiviral efficacy against Mpox. Furthermore, we have gained valuable insights from the process of Mpox drug development, including strategies for repurposing drugs, the discovery of drug targets driven by artificial intelligence, and preclinical drug development. The purpose of this review is to provide readers with a comprehensive overview of the current knowledge on Mpox.

Subject terms

Drug discovery
Infectious diseases
https://doi.org/10.13039/501100001809 National Natural Science Foundation of China (National Science Foundation of China) 82002192 Shen Liang https://doi.org/10.13039/501100003819 Natural Science Foundation of Hubei Province (Hubei Provincial Natural Science Foundation) 2022CFB539; 2022CFD107 Shen Liang Young and middle-aged Talents Project of Hubei Provincial Education Department (Q20222605), Scientific Research Ability Cultivation Fund of Hubei University of Arts and Science (2021KPGJ06), Science and Technology Plan (in the field of Medical and health care) of Xiangyang (2022YL05B; 2022YL12A).issue-copyright-statement© West China Hospital, Sichuan University 2023
==== Body
pmcIntroduction

Mpox (formerly monkeypox) is an emerging zoonotic disease caused by Mpox virus infection, which affects both humans and animals.1,2 The virus was first discovered in monkeys in 1958 and has since been detected in a variety of animal species.3 The first human case of Mpox infection was diagnosed in 1970 in the Republic of the Congo, located in Central Africa.4–6 Subsequently, Mpox has predominantly circulated in Central and West Africa, with transmission occurring between animals (primarily primates and rodents), as well as between animals and humans, and through human-to-human contact.7–9 In recent years, the rapid globalization, population movement, and deepening trade networks have contributed to the international dissemination of Mpox, resulting in outbreaks in various countries worldwide.10–12 Notably, in 2022, a global outbreak of Mpox affected 110 countries and regions.13 Although the World Health Organization declared that Mpox outbreaks no longer constituted an “a Public Health Emergency of International Concern in May 2023,”14 it is important to highlight that certain regions in Asia have experienced a rise in Mpox cases due to the virus’s rapid evolution and increased international travel (Fig. 1).15–17 Cases of Mpox virus infection have been reported in cities such as Beijing, Guangzhou, and Shenyang.18 With the continuous increase in the number of infected patients, Mpox, a disease that was previously neglected, has re-entered the public attention.19 To effectively combat the disease, a renewed comprehension of Mpox is necessary. This review presents a comprehensive overview of Mpox, including its transmission patterns, pathogenesis, genome organization, and antiviral drugs that have been studied for their activity against Mpox over the past few decades, both in vivo and in vitro. Additionally, it provides helpful insights for the prevention and control of worldwide Mpox outbreaks by summarizing the valuable experiences gained from the development of anti-Mpox strategies, such as drug repurposing, drug target discovery, and the identification of potential drug targets.Fig. 1 The timeline of the historical review and major milestones in Mpox

Transmission

The natural hosts of Mpox virus include some rodents and primates in central Africa. Early human infections are typically linked to contact with infected animals, including exposure to mucous membranes, body fluids, tissues, or consumption of undercooked meat. Transmission can also occur through scratches or bites from infected animals.20 Human-to-human transmission is believed to occur through direct contact with respiratory droplets from infected individuals.21–23 Furthermore, vertical transmission of Mpox virus can occur from infected mothers to their newborns. (Fig. 2a)24,25 This recent outbreak of Mpox infection was the largest reported epidemic outside of Africa, unlike previous outbreaks. In the past, Mpox infection was only diagnosed after contact with infected animals or traveling to regions affected by Mpox.26–28 However, in this current epidemic, most Mpox cases are not associated with contact with infected animals or travel, but with sexual contact between individuals.29 Over the past two years, the majority of reported cases of Mpox outbreaks have involved homosexual or bisexual males. A research study reported that 98% of cases were among homosexual or bisexual males, with 41% of them co-infected with human immunodeficiency virus (HIV). Additionally, 73% of the observed lesions occurred in the anal and genital regions.30,31 The incubation period of Mpox is ~7–14 days, with symptoms lasting for 14–21 days.32,33 The prolonged incubation period poses significant challenges for accurate diagnosis, potentially leading to delayed medical attention, disease progression, and further transmission of the virus.34,35Fig. 2 The epidemiological characteristics, pathogenesis, clinical diagnosis, and treatment of Mpox. a The transmission of Mpox occurs through animal-to-animal, animal-to-human, and human-to-human routes. b Clinical symptoms typically manifest after Mpox infection. c Symptoms of Mpox infection may vary based on the immune status and clinical treatment options and clinical treatment options are listed

Pathogenesis

Mpox is a self-limiting disease, and the severity of infection can be influenced by various factors, such as the specific viral strain, individual immune status, and potential complications that may arise.36 Common early symptoms of Mpox virus infection include pain, fever, fatigue, and lymphadenectasis, with significant inguinal lymphadenectasis often observed.37–40 The presence of lymphadenectasis can help to distinguish Mpox virus infection from other orthopoxviruses infection.41 Furthermore, understanding the transmission mode is essential in establishing effective measures to combat Mpox. Following exposure to the respiratory secretions or body fluids of Mpox patients, the Mpox virus enters nearby tissues through mucous membranes (such as ocular, respiratory, oral, urethral, and rectal) or broken skin.42,43 It then spreads throughout the body via tissue-resident immune cells and draining lymph nodes.42,44 This constitutes the latent period for Mpox virus infection, which typically lasts up to two weeks. Throughout this period, individuals infected with Mpox are generally asymptomatic and devoid of lesions. Following the latent period, individuals infected with Mpox virus begin to exhibit atypical symptoms, including fever and chills, headache, muscle pain, and lymphadenectasis. These initial prodromal symptoms of Mpox typically last for three days. After the fever and lymphadenectasis, rashes begin to appear on the head and face, and gradually spread throughout the body. The rash evolves from papules to vesicles and pustules, and ultimately forming crusts that heal, leaving behind scars. This progressive rash phase lasts about 2–4 weeks.43,45,46 In the current outbreak of Mpox among men who have sex with men (MSM), some unusual clinical signs have been observed with rashes appearing primarily around the genital or anal area and subsequently spreading throughout the body.27,47 Severe cases of Mpox virus infection can lead to complications such as hemorrhagic disease, necrotic disease, obstructive disease, inflammation of vital organs, and septicemia. The case fatality rate of Mpox in non-epidemic regions during 2022 was ~0.04%. (Fig. 2b)3,25,38,48–50 Immunocompromised individuals, including children, older adults, and those with immunodeficiencies (such as HIV patients and individuals using immunosuppressive medications), are more susceptible to experiencing these severe manifestations. In addition, immunocompromised individuals are more likely to contribute to the evolution of Mpox, making it increasingly adaptable to human hosts and resulting in widespread transmission (Fig. 2c).46,51–54

Virus morphology and genome

Mpox is caused by Mpox virus, a member of the genus orthopoxvirus in the family Poxviridae, is characterized by its brick-shaped or oval morphology with a diameter of ~200–250 nm.55,56 Its genome consists of a linear, double-stranded DNA with a length of ~197 kb and encoding about 180 proteins.57 Additionally, Mpox virus possesses dumbbell-shaped nucleocapsid enveloped by ovoid lipid-containing particles. The genomic structure of Mpox virus closely resembles that of other orthopoxviruses, characterized by a highly conserved central core region, variable regions at the left and right ends, and a tandemly repeated inverted terminal repeat. (Fig. 3)58,59 The central core region of Mpox virus shares more than 90% sequence homology with other orthopoxviruses, particularly within the open reading frame (ORF) located between C10L and A25R.57,60 Species and strain-specific characteristics of orthopoxviruses are often found in the variable regions at the ends of the genome. A better understanding about these ORFs may provide insights into its host tropism, pathogenesis, and differences in immune regulation.28 Based on a genomic and phylogenetic analysis conducted in 2022, the prevalent strain of Mpox virus was identified as belonging to the B.1 lineage of the West African clade. The B.1 lineage exhibits multiple mutations in genes associated with virulence, host recognition, and immune evasion.61 In comparison to previously obtained complete genome sequences of Mpox virus isolated in Nigeria from 2017 to 2018, the Mpox virus strains that emerged in 2022 exhibited a higher number of single nucleotide polymorphisms (SNPs). The Mpox virus strain isolated in 2022 exhibit ~50 SNPs, indicating an approximately 6–12-fold increase in the predicted substitution rate of Mpox virus compared to the strains isolated from 2018-2019 (1–2 nucleotide substitutions per genome every year).62,63 The functional significance of these mutations is yet to be fully understood, but this high mutation rate may help explain the sudden appearance and heightened transmissibility of Mpox virus in non-endemic regions.Fig. 3 The genome structure and potential antiviral targets of Mpox virus. The Mpox virus genome consists of a double-stranded linear DNA comprising approximately 196,858 base pairs. It consists of a central recognition region, two variable region, and two terminal inverted terminal repeats (ITRs) (Monkeypox virus strain Zaire, GenBank accession number: AF380138.1, web link: https://www.ncbi.nlm.nih.gov/nuccore/17529780). In the genome map, target genes implicated in the interaction between Mpox virus and antiviral drugs are listed. Most essential genes are located in the central region of the genome

The life cycle of Mpox virus and the discovery of anti-Mpox virus drugs

The process of Mpox virus infection and replication can be summarized into three distinct stages: 1) virus invasion; 2) virus replication and synthesis; 3) virus assembly, maturation and release.64–66 Targeting any stage of the Mpox virus lifecycle holds promise for the development of effective antiviral interventions against Mpox virus.

Anti-Mpox virus drugs targeting the invasive phase

The development of antiviral drugs begins with a thorough understanding of the complete life cycle of the virus (Fig. 4). In the early stages of Mpox virus infection, two distinct infectious viral particles are present: extracellular enveloped virions (EEV) and intracellular mature virions (IMV).67 These viral particles vary in surface glycoprotein and envelope membrane composition, with IMV exhibiting a single-membrane structure and EEV possessing a double-membrane structure. IMV are released only upon cell lysis and enters host cells through direct fusion and endocytosis,68,69 while EEV enters via membrane fusion.70–72 IMV are the most abundant viral particles in terms of quantity, due to the absence of a lipid membrane, which gives them a simpler and more robust structure.73 This enhances their resistance to external damage, prolonging their survival time outside the host. However, the exposed surface proteins of IMV trigger higher production of neutralizing antibodies and activate complement responses.74–76 Additionally, these exposed surface proteins enhance the recognition and inactivation of Mpox virus by immune cells. In contrast, EEV possesses an additional lipid membrane layer on their surface, enabling better intracellular dissemination.69 The pox virus can utilize lipid rafts on the lipid membrane to enter host cells, and cholesterol is one of the important components responsible for maintain the structure and function of lipid rafts.77,78 Amphotericin B, a long-standing antibiotic used for the treatment of fungal infections, can sequester cholesterol within host cell membranes, disrupting the integrity of lipid raft and potentially inhibiting Mpox virus infection.79 Additionally, cholesterol-lowering drugs such as statins and PCSK9 inhibitors may exhibit antiviral activity by modulating cellular cholesterol levels.80 Mpox virus attaches to mucous membranes and damaged skin, where a high concentration of glycosaminoglycans (GAGs) are present. GAGs serve as primary attachment receptors for host cells. EEV particles of Mpox virus interact with GAGs and enter host cells. Marine sulfated polysaccharides are natural analogs of GAGs that competitively bind to the host cell membrane surface, thereby preventing the attachment and entry of Mpox virus.Fig. 4 The life cycle of Mpox virus replication in hosts and potential targets for anti-Mpox virus drugs. The complete life cycle of Mpox virus infection: from entry into host cells to excretion. Briefly, both EEV and IMV viral particles penetrate the host membrane through membrane fusion and endocytosis. Mpox virus viral particles utilize glycosaminoglycans as host receptor. IMV particles enter the cytoplasm and are transported to the perinuclear replication factory via microtubules. The released Mpox virus genome serves as a template for DNA replication. Furthermore, IMV are enveloped by the Golgi apparatus to form IEV, and are transported to the cell surface via actin or microtubules. Part of the important drugs targeting each stage of the replication process are listed. EEV extracellular enveloped virions, IMV intracellular mature virions, IEV intracellular enveloped virions, IV immature virion

Since no specific receptor for Mpox virus on the host cell membrane has been found so far, several envelope proteins that play a key role in the invasion of host cells by Mpox virus, may be attractive targets for the development of anti-Mpox virus drugs. He et al. evaluated the binding capacity of eight marine sulfated polysaccharides to the surface envelope protein A35R of Mpox virus using surface plasmon resonance technology. The research findings indicated that some sulfated polysaccharides exhibited competitive binding effects and anti-Mpox virus activity.81 In another study, Li et al. inoculated BALB/c mice with recombinant A35R protein and purified the A35R immune serum, which showed high neutralizing activity against two types of vaccinia virus (VACV)-EEV.82 Moreover, several IMV surface membrane proteins, including I5L, E8L, and A43R have been identified through whole-genome sequencing, and may facilitate the entry of Mpox virus into host cells through receptor and membrane fusion.57,60 Although the exact mechanisms of interaction between these proteins and the host are not fully understood, they could potentially serve as targets for future anti-Mpox virus discovery. Further research is needed to unravel the specific roles of these proteins in Mpox virus infection.

Antiviral drugs that influence viral replication and synthesis

After IMV or EEV enter the host cell, the exposed viral core is transported to the periphery of the cell nucleus through microtubule structures at an average speed of 52 μm/min.83 The viral core consists of the central viral genome and an enveloped nucleocapsid. The mechanism of nucleocapsid uncoating involves ubiquitination of the nuclear capsid proteins and degradation by proteasomes.84–86 Once uncoating is completed, the Mpox virus genome begins efficient replication, rapidly amplifying like a factory.87–91

Currently, researchers are devoted to developing anti-Mpox drugs by interfering with the DNA or RNA synthesis of the viral genome.92 Nucleoside analogs are chemical compounds that have a similar structure to naturally occurring nucleosides. These drugs competitively bind to the viral DNA or RNA polymerase, disrupting the replication process by causing termination of the DNA or RNA chain synthesis. Due to their ability to inhibit viral replication, these drugs often exhibit broad-spectrum antiviral activity.93,94 Cidofovir, a non-cyclic monophosphate nucleoside analog, can be used for the treatment of orthopoxviruses and demonstrate potent antiviral activity in vitro (Mpox virus, effective concentration half maximal (EC50) = 2.52 μg/mL, Selectivity index (SI) = 15, in human embryonic lung fibroblasts) and in vivo (Mpox virus, 5 mg/kg, cynomolgus macaques, intraperitoneal injection; Mpox virus, 5 mg/kg, human, intravenous).95–98 Following the Mpox outbreak in 2022, Cidofovir was rapidly employed in clinical trials for the treatment of Mpox99–101 However, Cidofovir is a divalent anion with low bioavailability. In patients with impaired renal function or undergoing renal replacement therapy, its metabolites can accumulate in proximal renal tubular cells, leading to kidney damage.102–104 In order to overcome the limitations of Cidofovir, its derivative Brincidofovir has been developed. Brincidofovir has been modified using lipid conjugation technology, resulting in improved cellular uptake and conversion capabilities, it was approved by the FDA in 2021 for the treatment of smallpox.105 Unlike Cidofovir, Brincidofovir does not require metabolism through the renal anion transport system, thus exhibiting higher bioavailability and no significant nephrotoxicity in vitro (VACV, EC50 = 0.19 μM, in vero cells) and in vivo (Mpox virus, 10 mg/kg, mice, gastric gavage; Mpox virus, 200 mg, human, oral).105–109 However, Brincidofovir still presents some adverse reactions such as gastrointestinal reactions and liver function injury.101,110 Apart from Brincidofovir, other compounds based on structural modifications of Cidofovir have been developed.111,112 For instance, NPP-669 is synthesized by linking a long-chain sulfonate to Cidofovir. This modification improves its solubility in water and affinity for lipid through alkyl chain modification. As a result, this structural modification enhances the metabolic stability and bioavailability while reducing nephrotoxicity. It has shown enhanced antiviral effectiveness in vitro (vaccinia, EC50 = 8.95 μM, in HFF cells) and in vivo (cytomegalovirus, 3 mg/kg, mice, intraperitoneal injection).113 Ribavirin, a well-known nucleoside analog, blocks viral nucleotide synthesis and thus inhibits viral replication and transmission. It has broad-spectrum antiviral efficacy against various DNA and RNA viruses, including Mpox virus. Studies have shown that ribavirin can impede the replication of orthopoxviruses in vitro (Mpox virus, EC50 = 5.9 μg/mL, in Vero cells) and in vivo (cowpox virus, 50 mg/kg, mice, subcutaneous injection).114,115 However, further clinical studies are needed to assess its effectiveness in Mpox patients are needed. Although nucleotide analogs possess potent antiviral effects, they also have the potential to induce viral resistance. Recently, resistant Mpox virus strains to Cidofovir have been identified.116–118 Consequently, researchers are currently focused on the development of new nucleotide analogs such as KAY-2–41, a novel guanosine analog developed by Sophie et al. This analog exhibits potent antiviral activity against VACV in vitro (VACV-WR, EC50 = 0.8 μM, SI = 18, in human embryonic lung cells) and in vivo (VACV-WR, 50 mg/kg, mice, intraperitoneal injection), remaining effective against Cidofovir-resistant strains.119,120 This discovery provides a new therapeutic approach for nucleotide-resistant Mpox virus strains that are currently in use. However, further research and evaluation are needed for the clinical application of this novel nucleotide analog. The DNA-dependent RNA polymerase (DdRp) plays a crucial role in catalyzing the replication process of DNA viruses in the cytoplasm. Due to its biological significance, DdRp is considered a potential therapeutic target for Mpox virus. Through computer modeling of DdRp, along with techniques such as molecular dynamics simulations, docking, and computational screening, potential inhibitors of DdRp can be efficiently identified. Several small molecule compounds with inhibitory activity against DdRp have been discovered through computer-assisted drug design.121–123 However, further researches are needed to validate these identified candidate compounds, evaluate their safety and effectiveness, and ultimately progress them to the clinical application stage. The endoplasmic reticulum (ER) plays a crucial role in enveloping and stabilizing the viral genome. Electron microscopy observations have shown that the replication factory is surrounded by a significant amount of ER membrane. The ER plays a key role in the synthesis of viral membrane proteins.124,125 Subsequently, these membrane proteins, together with other viral structure proteins, enter into the viral factory, encapsulate the core genes, forming crescent-shaped structures.125,126 Moreover, the presence of the ER is important for maintaining the stability of the viral genome. Studies have indicated that ionomycin disrupts the integrity of ER in vitro, resulting in the inability of ER membrane proteins to enclose the exposed genome. This exposure triggers an immune response, leading to the degradation of viral DNA and significantly impacting VACV DNA replication.127 This discovery highlights the essential role of the ER in maintaining Mpox virus genome stability and facilitating viral replication. Based on these findings, compounds that effectively inhibit the formation of ER membrane proteins could also serve as potential antiviral drugs against Mpox virus.

Antiviral drugs that affect virus assembly, maturation, and release

Within the replication factory, these crescent-shaped structures develop into ellipsoidal or spherical shapes, representing immature virion (IV) particles.56,127 IV particles undergo the proteolytic cleavage of several capsid proteins and the condensation of the core, resulting in the formation of mature virus particles known as IMV. These IMV are abundant within the host cells. As IMV proliferate, they cause the lysis of the host cells, subsequently releasing IMV viral particles. Additionally, a portion of the IMV exits the virus factory through the microtubule organizing center and becomes enveloped by the trans-Golgi network (TGN) or the nuclear membranes, forming intracellular enveloped virus (IEV).128–131 Compared to the single-layered membrane structure of IMV, IEV possesses a three-layered membrane structure. During the early stage of infection, a majority of IMV are enveloped to form IEV. However, in the later stages of infection, IMV become the predominant form, possibly due to the depletion of TGN and nuclear membranes.132,133 Once IEV reach the peripheral region of the cell, the viral envelope fuses with the host cell membrane, forming cell-associated enveloped viruses (CEV) through the process of exocytosis.134 Virus particles remaining on the surface of the host cell are referred to as CEV, whereas those released into the extracellular environment are referred to as EEV.135 The ratio of EEV to CEV depends on the specific virus strain and host cell type. While the mechanism by which EEV released from infected cells further infect neighboring cells is not fully understood, researchers have discovered that the actin tails can form and extend a long distance outside the cell. EEV can utilize actin tails to enter adjacent cells, establishing bridges between the actin tails and neighboring cells, thereby facilitating efficient viral spread.136–138

In order to reach the cellular plasma membrane, the release of viruses requires the involvement of the actin cytoskeleton.139 Currently, two mechanisms have been proposed to explain how IEV traverse the actin cytoskeleton. The first mechanism is actin polymerization-induced assembly. Upon viral infection, host cells trigger the polymerization of actin, resulting in the formation of filamentous structures known as actin tails. Failure to form actin tails hinders virus migration, adhesion, and intercellular spread. Several studies suggest that tyrosine phosphorylation plays a pivotal role in the formation of actin tails.140,141 The second mechanism is microtubule transport. IEV reach the cell surface through microtubule-mediated transport. Studies conducted by Hollinshead et al. observed the movement trajectory of viral particles labeled with green fluorescent protein.142 They found that viral particles co-localized with microtubules and exhibited an average velocity of 60 μm/min, consistent with the speed of microtubule transport. This speed far exceeds the transport rate of actin tails (2.8 μm/min).143,144 The movement of viral particles to the cell surface can be hampered by the microtubule-depolymerizing drug nocodazole in vitro.145–147 Based on this evidence, it is evident that microtubule transport plays a crucial role in the externalization of IEV to the cell surface. Disruption of microtubule structures may contribute to reducing the export of virus particles and inhibiting the spread of infection. As we mentioned earlier, the actin tails play an important role in the process of Mpox virus infecting of neighboring cells. Several drugs have been reported to inhibit the formation of actin tails, including the anti-cancer drug imatinib mesylate, which has shown anti-orthopoxvirus activity in vitro.148 Furthermore, a compound named PA104, identified by Lalita., has been shown to significantly inhibit the formation of actin tails, thereby reducing viral release and spread in vitro (VACV, EC50 = 0.8 μM, SI > 800, in BSC40 cells).149 Epidermal growth factors (EGFs) encoded by orthopoxviruses, play a crucial role in intercellular virus transmission.150,151 EGF can activate the EGFR/MEK/FAK signaling pathway, promoting intercellular virus transmission and facilitating rapid movement of infected cells.152 This increases the likelihood of contact between infected and uninfected cells, ultimately enhancing the transmission efficiency of orthopoxviruses.153,154 Experimental findings demonstrate that the use of EGFR inhibitor gefitinib and MEK inhibitor effectively reduces the area of virus-infected plaques in vitro (VACV, EC50 = 4.93 μM, in Hep2 cells).155 Notably, gefitinib reduces actin tail formation by 1.6-fold and decreases infected cell migration efficiency by fourfold.153

The viral-encoded membrane proteins of orthopoxviruses also play a significant role in viral transmission. Research has demonstrated that the Mpox virus A36R protein is crucial role in intercellular virus transmission and the release of EEV into the surrounding environment.156 Mohammad et al. identified three peptides that effectively targeting A36R have been identified and exhibit effective antiviral activity against Mpox virus. These peptides show a high affinity for A36R while being non-allergenic and non-toxic.157 Furthermore, a study on vaccinia virus revealed that the absence of A33R and A34R proteins increases EEV production,158 while the absence of A36R and B5R proteins decreases EEV production.159 This suggests that Mpox virus-encoded proteins with homology with A36R or B5R could potentially be valuable antiviral targets for future therapeutic strategies against Mpox virus. The VP37 protein, encoded by the F13L gene, is a catalytic protein involved in the intracellular envelopment of mature viral particles.160–162 It is widely distributed and highly conserved among orthopoxviruses, playing a crucial role in the in the formation of IMV within the TGN.160 It is essential for the virus’s pathogenicity and infectivity. Deletion of the F13L gene hinders the membrane envelopment process of orthopoxviruses, limiting their further spread.163 Tecovirimat, initially named ST-246, is a compound discovered through high-throughput screening (HTS) that exhibits potent antiviral activity against Mpox virus in vitro (Mpox virus, EC50 = 0.01 μM, in Vero cells) and in vivo (Mpox virus, 10 mg/kg, cynomolgus macaques, gavage; Mpox virus, human, 600 mg bid, oral).164–167 Tecovirimat functions by inhibiting the synthesis of the VP37 protein, thereby impeding the maturation process of orthopoxviruses and disrupting their envelopment and release.168–170 Tecovirimat primarily restricts intercellular virus spread without affecting the viral replication process. It has been identified as one of the most effective drugs against orthopoxviruses. Following the Mpox outbreak in 2022, the U.S. Food and Drug Administration granted emergency approval for Tecovirimat as a therapeutic drug for Mpox, demonstrating its promising clinical efficacy.171 Between May 2022 and February 2023, Germany reported 12 severe cases of Mpox, in patients with either severe immunosuppression due to HIV infection (CD4 + T cell count below 200/μL) or significant systemic involvement (over 100 skin lesions). These patients underwent treatment with tecovirimat, and clinical outcomes revealed complete recovery in all patients, with Tecovirimat exhibiting excellent tolerability.172 In addition to Tecovirimat, another compound called NIOCH-14, serving as a precursor to Tecovirimat, has shown specific antiviral activity against orthopoxviruses and shares structural similarity with Tecovirimat in vitro (Mpox virus, EC50 = 0.013 μg/mL, in Vero cells) and in vitro (Mpox virus, 40 mg/kg, marmot, oral). Unlike tecovirimat, NIOCH-14 offers a simpler synthesis route, thereby reducing costs and technical requirements. This natural advantage makes NIOCH-14 promising candidate for future wide-ranging applications.100,173–175 The current round of Mpox outbreak is highly mutable and still evolving. Although Tecovirimat is effective in current clinical use, it may pose a risk of resistance in the future. Discovering drugs with a new mechanism of action could provide a solution to the drug resistance problem. PA104 suppressed the formation of extracellular virus particle and viral propagation by inhibiting actin tail formation. Its mechanism of action differed from that of Tecovirimat. Of note, PA104 has demonstrated the ability to inhibit the replication of Tecovirimat-resistant VACV strains in vitro.149

Immunothreapy in Mpox

Mpox virus-induced immunopathology leads to adverse outcomes in clinical, and immunotherapy for Mpox has the potential to reduce severe cases. Antibody-based therapeutics, immune cell, Immune effector molecules, and Modulation of cellular signal transduction are potential immunotherapies. Combination antiviral drugs with immunotherapy may be more effective and provide greater clinical benefit than single antiviral therapy alone.176–178

Immune globulin and antibodies

Antibody-based therapeutics have shown significant progress in treating certain infectious diseases and currently being actively explored.176,179 Immune globulin, convalescent plasma, and neutralizing antibodies offer promising options as adjunctive treatments for cases with insufficient antiviral drug efficacy in severe patients.180–182 Notably, individuals who have been previously vaccinated with the smallpox vaccine produce more neutralizing antibodies that may be cross-protective against Mpox virus infection.183 Thus, some countries have approved the intravenous administration of vaccinia immune globulin (VIGIV) for managing complications associated with smallpox vaccination.184 For individuals with severe T cell functional immunodeficiency due to contraindications to smallpox vaccination, VIGIV can be considered as a prophylactic measure in vitro (5 mg, incubated with VACV) and in vivo (VACV, 400 mg/kg, mice, intravenous) and in one clinical case (6000 U/kg, single-dose intravenous).185,186 Although convalescent plasma (CP) therapy shows therapeutic potential for other infectious viruses,187,188 there is currently no available literature regarding its use for the treatment of Mpox infection.176

Li et al. demonstrated that monoclonal antibodies (mAbs) targeting the specific proteins (A29L and A35R) of the Mpox virus effectively neutralized orthopoxviruses, including VACV. These mAbs also showed protective effect in mice, resulting in reduced viral titers and alleviation of lung injury.82 Gilchuk et al. identified a large number of orthopoxvirus-specific mAbs from the blood cells of human subjects with a history of prior orthopoxvirus vaccination or infection, and of which 16 mAbs had neutralizing activity against Mpox were identified. Moreover, mAbs targeting A33, L1, A27, or H3 antigens exhibited the broadest cross-neutralizing activity against VACV and Mpox virus. In vivo experiments confirmed that a combination of mAbs with high neutralizing activity provides efficient protection against lethal doses of VACV infection in mice (VACV, 1.2 mg mAbs, intraperitoneal injection), compared to VIGIV. This protective effect was observed even in severe combined immune-deficiency mouse models.181 Therefore, mAbs drugs are most likely to provide effective clinical treatment outcomes in the development of anti-Mpox treatments compared to VIGIV and CP, which have uncertain efficacy.

Immune cells

Mpox virus enters the human body through mucous membranes or compromised skin, resulting in infection of resident immune cells and antigen-presenting cells in the tissues.189–191 Subsequently, Mpox virus rapidly replicates in draining lymph nodes and disseminates through the lymphatic system,192,193 explaining the characteristic lymph node enlargement observed in Mpox virus infections. Innate immune cells act as the first line of defense against viral infections and are primary targets for viral assault. During the early stages of Mpox virus infection, monocytes are recruited to the infection site and become early targets for viral infection.194 The level of Mpox virus antigens detected in monocytes can serve as an indicator of infection severity and prognosis. Additionally, natural killer (NK) cells play a crucial role in generating a robust immune response following Mpox virus infection. Despite an increase in the abundance of NK cells in Mpox virus-infected individuals, their migration, degranulation, and effector molecule release capabilities are significantly impaired. Patricia’s study demonstrated that the injection of in vitro expanded NK cells into mice infected with vaccinia virus resulted in significantly prolonged mouse survival and enhanced secretion of IFN-γ by NK cells.195,196 T cells, another vital immune cell type, possess cytotoxic functions and the ability to regulate disease severity. Individuals with acquired immunodeficiency are at high risk of severe infections when co-infected with Mpox virus, often requiring active medical intervention rather than spontaneous resolution.197,198 Furthermore, individuals with compromised immune function are more susceptible to severe disease and mortality during Mpox virus infection. Other immune cell types, such as dendritic cells and innate lymphoid cells, also undergo alterations during Mpox virus infection.199 Understanding the characteristics and transformations of diverse immune cells during Mpox virus infection is important for gaining insights into the immune response and developing immunotherapy.

Immune effector molecules and immunomodulators

The response of immune effector molecules during Mpox virus infection—plays a crucial role in disease progression and severity. At the beginning of infection, the Mpox virus can suppress the expression of chemokines, resulting in a decrease in effector molecule expression like IFN-γ and TNF-α. This inhibition in T-cell activation hinders the initiation of humoral immune response, allowing the virus to evade the immune system much easier. However, severe Mpox infection often leads to a cytokine storm in later stages. This results in an increase in Th2-associated cytokines and a decrease in Th1-associated cytokines, characterized by increased expression of IL-2, IL-4, and IL-8 and a reduction in TNF-α, IL-2, and IL-12 (Fig. 5). By regulating these immune effectors, Mpox virus suppresses the antiviral immune response and disrupts the host immunity. Ribavirin, in addition to blocking viral nucleotide synthesis, also acts as an immunomodulator. It regulates T-cell polarization, and can enhance the release of interferon-gamma (IFN-γ) and T-bet, which are associated with Th1 response, in the serum of patients infected with hepatitis viruses. Simultaneously, ribavirin suppresses the release of GATA binding protein 3 and IL-4, which are related to Th2 response, promoting T-cell polarization towards Th1 and strengthening the antiviral action of the immune system.200–202 Ribavirin also stimulates the generation of central memory T-cells and Tregs.203,204 Pidotimod is an immunomodulator used as an adjunctive therapy for respiratory or urinary tract infections.205 It promotes non-specific and specific immune responses by activating NK cells, stimulating lymphocyte proliferation, and inducing the release of IL-1β and IFN-γ.206–209 Thymosin is an exogenous polypeptide with immunoregulatory effects that promote T cell differentiation, development, and maturation.210,211 Additionally, Thymosin can indirectly enhance the immune responses of other immune cells.212,213 Nevertheless, the clinical use of pidotimod and thymosin preparations in Mpox virus-infected patients has not been reported and requires further investigation to validate their efficacy. Although immunomodulators cannot directly elicit an anti-Mpox virus effect, they have the potential to improve the immune system, which may help reduce the development of severe manifestations and decrease mortality rates.210,211,214 Exploring the combination of immunomodulators with other anti-Mpox virus medications may be a promising avenue for further investigation.Fig. 5 The host cell immune response after Mpox virus infection. The Mpox induces specific and non-specific immune responses after infection. Briefly, upon entry of Mpox virus into host cells, mononuclear phagocytes and neutrophils initiate recruitment and increased proliferative infiltration, other antigen-presenting cells (such as dendritic cell) become activated, leading to the release of effector molecules and chemokines, while other cells (T cells, B cells, NK cells and the complement system) of the immune system also begin to exert their corresponding effector functions. IL interleukin, Th helper T cell, IFN Interferon, ADCC antibody-dependent cell-mediated cytotoxicity

Modulation of the virus-induced cellular signal transduction

Mpox virus infection induces immune responses while also regulating cellular signal transduction.215,216 One example is the presence of a Mpox virus-encoded Bcl-2-like protein, which regulates the intrinsic apoptotic pathway. Additionally, the SPI-2 protein, encoded by the B12R gene,217 inhibits both caspase-1 and caspase-8, thereby disrupting the pyroptosis or apoptosis pathway,218,219 respectively. However, active induction of pyroptosis can be achieved by using nigericin, an inflammasome activator and pyroptosis inducer, as a strategy against Mpox infection. In an in vitro study conducted by Chad et al., Hela cells were infected with vaccinia virus and treated with Nigericin in vitro (VACV, EC50 = 7.9 nM, SI = 1038, in Hela cells).220 The findings demonstrated that Nigericin effectively reduced the viral titers and showed a stronger antiviral effect and lower EC50 values compared to the control group treated with Cidofovir. Protein kinases play a key role in regulating signal transduction pathways.221,222 Raghav et al. conducted an analysis to explore the interactions between Mpox virus and host proteins in order to further investigate the defense mechanisms triggered by Mpox infection. Their findings show the important role of the mitogen-activated protein kinase (MAPK) signaling pathway in the response to Mpox infection.216 Inhibition of the thymidine kinase enzyme, which is activated by MAPK, led to a significant reduction in viral replication.223–225 This evidence supports the potential of targeted therapies against MAPK signaling pathway as a promising strategy to combat Mpox (Fig. 6).224,226Fig. 6 Illustrates the signaling pathways associated with the targeted actions of certain drugs following Mpox virus infection. Upon infection, Mpox inhibits pyroptosis, impeding the formation of inflammasomes and activation of caspase-1. This blockade prevents pyroptosis and hampers the adequate activation of the immune response against Mpox infection. However, nigericin, an activator of NLRP3 can induce pyroptosis in host cells, making it a promising candidate for an anti-Mpox drug. Moreover, tBID, a protein involved in apoptosis, is suppressed upon Mpox virus infection, thereby inhibiting both intrinsic and extrinsic apoptotic pathways and ensuring the survival of Mpox virus within host cells. This mechanism can be exploited by employing apoptosis inducers as a strategy to combat Mpox virus. Furthermore, Mpox virus infection triggers the binding of EGF and EGFR, activation downstream MAPK and MEK signaling pathways, leading to the release of inflammatory and chemotactic factors, and modulation of immune cells. That is, EGFR inhibitors like gefitinib may exhibit significant anti-Mpox activity

Prospect and challenges

With the global cessation of smallpox vaccination administration, the proportion of individuals with cross-immune protection against Mpox virus has rapidly declined, rendering Mpox a potential bioterrorism threat. While a few anti-Mpox drugs, such as Tecovirimat, have been clinically proven to be effective, relying solely on them would be unwise. Despite Mpox virus belonging to the DNA virus family, it exhibits significantly higher genomic variability due to increased nucleotide polymorphism. The rapid population mobility and increased international travel have facilitated the continuous spread of Mpox virus among populations, further increasing its potential for mutation.11,227,228 These factors contribute to increased variability, drug resistance, and the emergence of multidrug-resistant strains of Mpox virus.229 Moreover, currently available drugs face certain limitations that impede their clinical applications. For example, Cidofovir has low bioavailability and carries the risk of renal damage, while Cidofovir and Brincidofovir pose potential threats to hematopoietic and liver functions. There is an urgent need to develop novel anti-Mpox virus drugs.230

The lengthy and costly nature of drug development, combined with numerous uncertainties, has led to the exploration of drug repurposing strategies as a more efficient and economical approach.110,231–233 HTS of marketed drugs or clinically established medications has the potential to expedite the identification of antiviral agents, thus saving valuable time.234–236 For instance, the potential antiviral drug ribavirin has demonstrated therapeutic effectiveness against Mpox infection. Similarly, the widely used EGFR inhibitor gefitinib has shown promising antiviral activity against Mpox virus in addition to its approved indication for late-stage non-small cell lung cancer. However, drug repurposing efforts still heavily rely on serendipitous discoveries. Historically, drug development has been predominantly confined to laboratory settings. However, advances in computer science and computational drug design have significantly accelerated the discoveries in drug repurposing.237–239 Computer-aided drug discovery (CADD) techniques encompass the following three main directions: 1) High-throughput library screening of small molecule libraries, such as the discovery and development of Tecovirimat based on the VP37 protein. 2) Structural optimization based on existing drugs, such as NPP669, which involves alkyl chain modifications based on Cidofovir, resulting in overall improved pharmacological properties compared to Cidofovir. 3) Directly targeting functional sites for novel drug design, such as DdRp, which usually serves as a target for antiviral CADD.

In recent years, there has been relatively little attention on the Mpox outbreak in endemic area. However, the rapid spread of Mpox in non-endemic regions and its global impact have brought it back into the public attention. This particular outbreak of Mpox appears to exhibit distinct epidemiological characteristics and transmission dynamics compared to previous outbreaks.63 Previous knowledge suggested that the West African clade had weak transmission and pathogenicity compared to the Central African clade. However, the current situation reveals that the 2022-Mpox virus genome mutation and phylogenetic analysis indicate that this outbreak belongs to the B.1 lineage of the West African clade. The B1 lineage has exhibited mutations in virulence proteins, host recognition proteins, and immune evasion.240 APOBEC3 is an important enzyme that demonstrates antiviral activity against HIV, Hepatitis B Virus, Epstein-Barr virus, and other viruses through its functional cytidine deaminase activity.241,242 APOBEC3-mediated viral genome editing may be characterized by compatible substitutions GA>AA and TC>TT. Isidro et al. discovered a significant increase in G-to-A and C-to-T mutations in the recent Mpox isolates, with 46 SNPs showing mutation bias, among which 26 and 15 substitutions were GA>AA and TC>TT, respectively.63,243,244 These unusual mutation biases and the abundance of A: T bases in Mpox virus indicate that specific mutations driven by APOBEC3 may further reduce the pathogenicity and symptoms caused by Mpox virus infection, facilitating covert transmission within populations, and indirectly contributing to the global epidemic of Mpox. Although further experimental validation is necessary to confirm Mpox virus mutations mediated by APOBEC3, it is undeniable that APOBEC3 is a promising host antiviral protein for research. Understanding the mechanism of mutations driven by APOBEC3 may help reveal the mysteries behind the pathogenicity transition of Mpox.245 Additionally, the development of anti-Mpox drugs targeting APOBEC3 may provide a new direction for future drug development.

The development of multi-omics technologies and HTS techniques has enabled precise identification and characterization of various molecular targets of Mpox virus, which is crucial for the development of novel anti-Mpox virus drugs targeting new mechanisms. Furthermore, multi-omics technologies have revealed the gene expression patterns during Mpox infection and identified specific receptors and pathways regulated during Mpox progression. By precisely modulating these receptors and pathways, it is possible to develop drugs for Mpox therapy. This study contributes to optimizing the chemical structure of drugs, enhancing their delivery and targeting, thereby improving treatment precision and reducing drug side effects (Table 1).Table 1 Anti-Mpox drugs and candidate compounds

	Name	Mechanism	Function	Clinical Use	
Targeting virus intrusion	Amphotericin B	Isolate cholesterol and destroy lipid rafts	Restrict Mpox virus entry	☒	
Cholesterol lowering drugs	
Glycosaminoglycan analog	Competitive binding to host cell membrane	Prevent the attachment and entry of Mpox virus	☒	
Targeting virus replication	Cidofovir	Competitive binding of DNA or RNA polymerase	Interference with viral DNA or RNA synthesis	☑	
Brincidofovir	☑	
NPP-669	☒	
KAY-2–41	☒	
Trifluridine	☑	
Ribavirin	☑	
Ionomycin	Destroy the integrity of Endoplasmic reticulum	Inhibit the viral genome envelope formation	☒	
Targeting virus assembly, maturation and release	Nocodazole	Promote microtubule depolymerization	Inhibit the movement of viral particles to the cell surface	☒	
Imatinib mesylate	Tyrosinase inhibition	Inhibit the actin tail formation	☒	
PA104	Inhibit the actin tail formation	Inhibit Mpox virus efflux	☒	
Tecovirimat	Inhibit vp37 protein synthesis	Inhibit the maturation and budding release of orthopoxviruses	☑	
NIOCH-14	☒	
Gefitinib	EGFR inhibition	Inhibit the actin tail formation	☒	
MEK inhibitors	MEK inhibition	Inhibit the actin tail formation	☒	
A36R polypeptide	Anti Mpox virus-A36R	Inhibit Mpox virus transmission and release	☒	
Immunoregulation	VIGIV	antigen binding	Prevent Mpox virus infection of target cells	☑	
Pidotimod	Enhancing specific and non-specific immunity	Enhance immune response	☒	
Thymopeptide	☒	
mAbs	Destroy virus particles	Prevent virus infection of cells	☒	
Nigericin	Activate IL-1β and IL-18	Induced pyroptosis	☒	
Imiquimod	TLR agonists and local immune activity enhancer	Stimulate cytokine production and activate local immunity	☒	

In recent years, AI, especially machine learning and deep learning methods, have increasingly been utilized in various stages of the drug development process, challenging the traditional paradigms of new drug discovery and design.246 By leveraging extensive compound data within libraries, AI enables efficient design and optimization of compounds targeting various Mpox virus homologous proteins. This approach facilitates the effective screening of optimal anti-Mpox virus drugs or the development of promising new candidate molecules, ultimately reducing the cost and time associated with drug development.247,248 However, it is important to note that no commercially available drugs have emerged from this approach yet, indicating the need for further technical advancements and breakthroughs in the field.249

In addition to the development of systemic anti-infective drugs, exploring local therapies for Mpox is crucial. Mpox infections can cause severe physiological and psychological trauma to the skin and eyes.250 This damage is often visibly evident and difficult to conceal. Skin lesions, for example, are a hallmark of Mpox infection and inflict immense pain on patients. The psychological trauma resulting from these skin injuries and subsequent scarring may surpass the physical harm. A distressing incident reported in 2017 by Dimie et al. highlighted the tragic suicide of a 34-year-old Mpox patient due to the psychological trauma endured post-infection.251 Therefore, addressing skin lesions during the course of Mpox infection is essential. Notably, the topical cream imiquimod has demonstrated particular efficacy in treating Mpox-induced skin lesions.252,253 The exact mechanism of action of imiquimod in the treatment of Mpox infections is not fully understood, although several potential mechanisms have been proposed. Imiquimod acts as an agonist for Toll-like receptor 7 (TLR-7) and Toll-like receptor 8 (TLR-8), triggering the nuclear translocation and transcriptional activity of nuclear factor κB (NF-κB). This activation leads to the release of downstream pro-inflammatory cytokines, enhancing the immune response against Mpox. Additionally, imiquimod acts as a direct local immune stimulant by stimulating the production of various cytokines, including IFN-γ, TNF-α, IL-1β, and IL-6. These cytokines play a crucial role in activating the innate immune system and promoting a localized immune response.254–256 Studies have shown that imiquimod can recruit plasmacytoid dendritic cells to the site of infection, thereby enhancing the antigen presentation process. Although ocular infections caused by Mpox are relatively rare, they may result in permanent visual impairment, including irreversible conditions such as corneal perforation. As a locally administered nucleoside analog, trifluridine eye drops are currently considered the most effective treatment for ocular Mpox infections. In addition to controlling Mpox proliferation in the eyes, trifluridine eye drops also help reduce the production of conjunctival secretions, thereby minimizing the risk of spreading the infection to others.

To address the widespread occurrence of Mpox, it is imperative to recognize it as a global public health concern. In addition to the development of therapeutic medications, emphasis must be placed on preventive measures. Prevention, especially among areas with active Mpox transmission and those in high-risk populations like HIV-infected MSM, is crucial.257 Vaccination is an effective strategy for preventing Mpox. Studies indicate indicates that vaccinia vaccine can offer partial protection against Mpox infection.258,259 However, the use of smallpox vaccines for Mpox prevention in epidemic regions limited due to potential risks for immunocompromised individuals, particularly those co-infected with HIV. First-generation vaccines like Dryvax and second-generation vaccines such as ACAM2000, which are live replicating vaccinia virus vaccines, can cause severe infections such as progressive vaccinia.260 The emergence of third-generation vaccines provides an alternative for this specific population. One example is Imvamune (also known as JYNNEOS) a non-replicating vaccinia vaccine that has been tested safe for HIV-infected patients. Animal models have shown that JYNNEOS also provides protection against Mpox.261 In 2019, the FDA approved JYNNEOS for preventing Mpox infection in high-risk populations aged 18 and above.262 Clinical evidence has demonstrated that JYNNEOS vaccination effectively prevents Mpox cases and reduce the incidence of severe illness.258,263,264 At the national and regional levels, enhancing public health investments, including environmental sanitation and disinfection, and establishing efficient case identification and contact tracing mechanisms, is essential. On an individual level, it is crucial to educate oneself about Mpox, maintain good personal hygiene, employ personal protective measures, and avoid contact with infection sources. Therefore, the most cost-effective method to reduce the incidence and transmission of Mpox is through implementing preventive measures rather than solely relying on the development of novel anti-Mpox drugs.

Conclusions

While some progress has been made in the development of drugs against Mpox, it is crucial to expedite the research progress. This will enable us to effectively combat potential long-term outbreaks and the emergence of drug-resistant Mpox virus strains. In the development of drugs against Mpox, the following aspects should be given priority: Firstly, improving the specificity and delivery efficiency of drugs is essential to ensure accurate targeting of the Mpox and efficient transmission to the infection site. Secondly, development anti-Mpox drugs that are less prone to resistance is necessary to prevent the gradual emergence of drug-resistant strains and ensuring sustained efficacy of treatment. Additionally, exploring the development of sequential and combination drug therapies should enhance effectiveness against different stages of Mpox infections and their variants. Lastly, attention should be paid to drug modifications to mitigate or eliminate toxicity, minimizing the adverse impact on patients during the treatment process. The early investment in drug development against Mpox is crucial in tackling the ongoing global Mpox outbreak. Accelerating progress in the development of effective anti-Mpox drugs will help prepare for future challenges and provide more reliable protection for public health.

Acknowledgements

This research was supported by National Natural Science Foundation of China (82002192), Natural Science Foundation of Hubei Province (2022CFB539; 2022CFD107), Young and middle-aged Talents Project of Hubei Provincial Education Department (Q20222605), Scientific Research Ability Cultivation Fund of Hubei University of Arts and Science (2021KPGJ06), Science and Technology Plan (in the field of Medical and health care) of Xiangyang (2022YL05B; 2022YL12A). Figures were created in BioRender.com.

Author contributions

J.J.L., H.X., C.H.W., M.J.T., Y.Y., W.J.T. and L.S. contributed to the conception of the review, J.J.L., H.X., C.H.W. and M.J.T. collected the information and wrote the manuscript. C.C.W., F.Y. and L.J.Y provided guidance on article writing and polishing. Y.Y., W.J.T. and L.S. contributed to the constructive discussions. All authors have read and approved the article.

Competing interests

The authors declare no competing interests.

These authors contributed equally: Junjie Lu, Hui Xing, Chunhua Wang, Mengjun Tang
==== Refs
References

1. McCollum AM Damon IK Human monkeypox Clin. Infect. Dis. 2014 58 260 267 10.1093/cid/cit703 24158414
McCollum, A. M. & Damon, I. K. Human monkeypox. Clin. Infect. Dis. 58, 260–267 (2014).24158414 10.1093/cid/cit703
2. Otu A Global human monkeypox outbreak: atypical presentation demanding urgent public health action Lancet Microbe 2022 3 e554 e555 10.1016/S2666-5247(22)00153-7 35688169
Otu, A. et al. Global human monkeypox outbreak: atypical presentation demanding urgent public health action. Lancet Microbe 3, e554–e555 (2022).35688169 10.1016/S2666-5247(22)00153-7
3. Cabanillas B A compilation answering 50 questions on monkeypox virus and the current monkeypox outbreak Allergy 2023 78 639 662 10.1111/all.15633 36587287
Cabanillas, B. et al. A compilation answering 50 questions on monkeypox virus and the current monkeypox outbreak. Allergy 78, 639–662 (2023).36587287 10.1111/all.15633
4. Carrubba S Novel severe oculocutaneous manifestations of human monkeypox virus infection and their historical analogues Lancet Infect. Dis. 2023 23 e190 e197 10.1016/S1473-3099(22)00869-6 36702137
Carrubba, S. et al. Novel severe oculocutaneous manifestations of human monkeypox virus infection and their historical analogues. Lancet Infect. Dis. 23, e190–e197 (2023).36702137 10.1016/S1473-3099(22)00869-6
5. Ladnyj ID Ziegler P Kima E A human infection caused by monkeypox virus in Basankusu Territory, Democratic Republic of the Congo Bull. World Health Organ. 1972 46 593 597 4340218
Ladnyj, I. D., Ziegler, P. & Kima, E. A human infection caused by monkeypox virus in Basankusu Territory, Democratic Republic of the Congo. Bull. World Health Organ. 46, 593–597 (1972).4340218
6. Foster SO Human monkeypox Bull. World Health Organ. 1972 46 569 576 4340216
Foster, S. O. et al. Human monkeypox. Bull. World Health Organ. 46, 569–576 (1972).4340216
7. Khodakevich L Jezek Z Messinger D Monkeypox virus: ecology and public health significance Bull. World Health Organ. 1988 66 747 752 2853010
Khodakevich, L., Jezek, Z. & Messinger, D. Monkeypox virus: ecology and public health significance. Bull. World Health Organ. 66, 747–752 (1988).2853010
8. Khodakevich L The role of squirrels in sustaining monkeypox virus transmission Trop. Geogr. Med. 1987 39 115 122 2820094
Khodakevich, L. et al. The role of squirrels in sustaining monkeypox virus transmission. Trop. Geogr. Med. 39, 115–122 (1987).2820094
9. Doty JB Assessing Monkeypox virus prevalence in small mammals at the human-animal interface in the Democratic Republic of the Congo Viruses. 2017 9 283 10.3390/v9100283 28972544
Doty, J. B. et al. Assessing Monkeypox virus prevalence in small mammals at the human-animal interface in the Democratic Republic of the Congo. Viruses. 9, 283 (2017).28972544 10.3390/v9100283
10. Bunge EM The changing epidemiology of human monkeypox—a potential threat? A systematic review PLoS Negl. Trop. Dis. 2022 16 e0010141 10.1371/journal.pntd.0010141 35148313
Bunge, E. M. et al. The changing epidemiology of human monkeypox—a potential threat? A systematic review. PLoS Negl. Trop. Dis. 16, e0010141 (2022).35148313 10.1371/journal.pntd.0010141
11. Meo SA Al-Khlaiwi T Al Jassir FF Meo AS Impact of traveling on transmission trends of human monkeypox disease: worldwide data based observational analysis Front Public Health 2023 11 1029215 10.3389/fpubh.2023.1029215 37388159
Meo, S. A., Al-Khlaiwi, T., Al Jassir, F. F. & Meo, A. S. Impact of traveling on transmission trends of human monkeypox disease: worldwide data based observational analysis. Front Public Health 11, 1029215 (2023).37388159 10.3389/fpubh.2023.1029215
12. Costello V Imported Monkeypox from International Traveler, Maryland, USA, 2021 Emerg. Infect. Dis. 2022 28 1002 1005 10.3201/eid2805.220292 35263559
Costello, V. et al. Imported Monkeypox from International Traveler, Maryland, USA, 2021. Emerg. Infect. Dis. 28, 1002–1005 (2022).35263559 10.3201/eid2805.220292
13. Alakunle EF Okeke MI Monkeypox virus: a neglected zoonotic pathogen spreads globally Nat. Rev. Microbiol. 2022 20 507 508 10.1038/s41579-022-00776-z 35859005
Alakunle, E. F. & Okeke, M. I. Monkeypox virus: a neglected zoonotic pathogen spreads globally. Nat. Rev. Microbiol. 20, 507–508 (2022).35859005 10.1038/s41579-022-00776-z
14. WHO Director-General’s opening remarks at the media briefing, https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing---11-may-2023 (2023).
15. Nuzzo JB Borio LL Gostin LO The WHO declaration of Monkeypox as a global public health emergency JAMA. 2022 328 615 617 10.1001/jama.2022.12513 35895041
Nuzzo, J. B., Borio, L. L. & Gostin, L. O. The WHO declaration of Monkeypox as a global public health emergency. JAMA. 328, 615–617 (2022).35895041 10.1001/jama.2022.12513
16. Sabeena S The changing epidemiology of monkeypox and preventive measures: an update Arch. Virol. 2023 168 31 10.1007/s00705-022-05677-3 36604361
Sabeena, S. The changing epidemiology of monkeypox and preventive measures: an update. Arch. Virol. 168, 31 (2023).36604361 10.1007/s00705-022-05677-3
17. Papukashvili D Strategy of developing nucleic acid-based universal monkeypox vaccine candidates Front. Immunol. 2022 13 1050309 10.3389/fimmu.2022.1050309 36389680
Papukashvili, D. et al. Strategy of developing nucleic acid-based universal monkeypox vaccine candidates. Front. Immunol. 13, 1050309 (2022).36389680 10.3389/fimmu.2022.1050309
18. China CDC: Monitoring of Monkeypox Epidemic in August 2023, https://www.chinacdc.cn/jkzt/crb/qt/szkb_13037/gwjszl_13092/202309/t20230908_269405.html (2023).
19. Adetifa I Muyembe JJ Bausch DG Heymann DL Mpox neglect and the smallpox niche: a problem for Africa, a problem for the world Lancet 2023 401 1822 1824 10.1016/S0140-6736(23)00588-3 37146622
Adetifa, I., Muyembe, J. J., Bausch, D. G. & Heymann, D. L. Mpox neglect and the smallpox niche: a problem for Africa, a problem for the world. Lancet 401, 1822–1824 (2023).37146622 10.1016/S0140-6736(23)00588-3
20. Harris E What to know about Monkeypox JAMA 2022 327 2278 2279 10.1001/jama.2022.9499 35622356
Harris, E. What to know about Monkeypox. JAMA 327, 2278–2279 (2022).35622356 10.1001/jama.2022.9499
21. Walter K Malani PN What is Monkeypox? JAMA 2022 328 222 10.1001/jama.2022.10259 35679066
Walter, K. & Malani, P. N. What is Monkeypox? JAMA 328, 222 (2022).35679066 10.1001/jama.2022.10259
22. Beeson A Mpox respiratory transmission: the state of the evidence Lancet Microbe 2023 4 e277 e283 10.1016/S2666-5247(23)00034-4 36898398
Beeson, A. et al. Mpox respiratory transmission: the state of the evidence. Lancet Microbe 4, e277–e283 (2023).36898398 10.1016/S2666-5247(23)00034-4
23. Upadhayay S Monkeypox infection: the past, present, and future Int. Immunopharmacol. 2022 113 109382 10.1016/j.intimp.2022.109382 36330915
Upadhayay, S. et al. Monkeypox infection: the past, present, and future. Int. Immunopharmacol. 113, 109382 (2022).36330915 10.1016/j.intimp.2022.109382
24. Adler H Taggart R Monkeypox exposure during pregnancy: what does UK public health guidance advise? Lancet 2022 400 1509 10.1016/S0140-6736(22)01794-9 36522201
Adler, H. & Taggart, R. Monkeypox exposure during pregnancy: what does UK public health guidance advise? Lancet 400, 1509 (2022).36522201 10.1016/S0140-6736(22)01794-9
25. Billioux BJ Mbaya OT Sejvar J Nath A Potential complications of monkeypox Lancet Neurol. 2022 21 872 10.1016/S1474-4422(22)00340-4 36115356
Billioux, B. J., Mbaya, O. T., Sejvar, J. & Nath, A. Potential complications of monkeypox. Lancet Neurol. 21, 872 (2022).36115356 10.1016/S1474-4422(22)00340-4
26. Durski KN Emergence of Monkeypox–West and Central Africa, 1970-2017 Morb. Mortal. Wkly Rep. 2018 67 306 310 10.15585/mmwr.mm6710a5
Durski, K. N. et al. Emergence of Monkeypox–West and Central Africa, 1970-2017. Morb. Mortal. Wkly Rep. 67, 306–310 (2018).10.15585/mmwr.mm6710a5
27. Wang Y Leng P Zhou H Global transmission of monkeypox virus-a potential threat under the COVID-19 pandemic Front. Immunol. 2023 14 1174223 10.3389/fimmu.2023.1174223 37215147
Wang, Y., Leng, P. & Zhou, H. Global transmission of monkeypox virus-a potential threat under the COVID-19 pandemic. Front. Immunol. 14, 1174223 (2023).37215147 10.3389/fimmu.2023.1174223
28. Kumar P Recent advances in research and management of human Monkeypox virus: an emerging global health threat Viruses. 2023 15 937 10.3390/v15040937 37112916
Kumar, P. et al. Recent advances in research and management of human Monkeypox virus: an emerging global health threat. Viruses. 15, 937 (2023).37112916 10.3390/v15040937
29. WHO: Multi-country monkeypox outbreak in non-endemic countries, https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON385 (2022).
30. Del Rio C Malani PN Update on the Monkeypox outbreak JAMA. 2022 328 921 922 10.1001/jama.2022.14857 35951336
Del Rio, C. & Malani, P. N. Update on the Monkeypox outbreak. JAMA. 328, 921–922 (2022).35951336 10.1001/jama.2022.14857
31. Aden D Zaheer S Kumar R Ranga S Monkeypox (Mpox) outbreak during COVID-19 pandemic-past and the future J. Med. Virol. 2023 95 e28701 10.1002/jmv.28701 36951352
Aden, D., Zaheer, S., Kumar, R. & Ranga, S. Monkeypox (Mpox) outbreak during COVID-19 pandemic-past and the future. J. Med. Virol. 95, e28701 (2023).36951352 10.1002/jmv.28701
32. Guarner J Del Rio C Malani PN Monkeypox in 2022—what clinicians need to know JAMA 2022 328 139 140 10.1001/jama.2022.10802 35696257
Guarner, J., Del Rio, C. & Malani, P. N. Monkeypox in 2022—what clinicians need to know. JAMA 328, 139–140 (2022).35696257 10.1001/jama.2022.10802
33. Nolen LD Extended human-to-human transmission during a Monkeypox outbreak in the Democratic Republic of the Congo Emerg. Infect. Dis. 2016 22 1014 1021 10.3201/eid2206.150579 27191380
Nolen, L. D. et al. Extended human-to-human transmission during a Monkeypox outbreak in the Democratic Republic of the Congo. Emerg. Infect. Dis. 22, 1014–1021 (2016).27191380 10.3201/eid2206.150579
34. Accordini S People with asymptomatic or unrecognised infection potentially contribute to monkeypox virus transmission Lancet Microbe 2023 4 e209 10.1016/S2666-5247(22)00379-2 36563704
Accordini, S. et al. People with asymptomatic or unrecognised infection potentially contribute to monkeypox virus transmission. Lancet Microbe 4, e209 (2023).36563704 10.1016/S2666-5247(22)00379-2
35. Reda A El-Qushayri AE Shah J Asymptomatic monkeypox infection: a call for greater control of infection and transmission Lancet Microbe 2023 4 e15 e16 10.1016/S2666-5247(22)00259-2 36209756
Reda, A., El-Qushayri, A. E. & Shah, J. Asymptomatic monkeypox infection: a call for greater control of infection and transmission. Lancet Microbe 4, e15–e16 (2023).36209756 10.1016/S2666-5247(22)00259-2
36. Mahmoud A Nchasi G Monkeypox virus: a zoonosis of concern J. Med. Virol. 2023 95 e27968 10.1002/jmv.27968 35770346
Mahmoud, A. & Nchasi, G. Monkeypox virus: a zoonosis of concern. J. Med. Virol. 95, e27968 (2023).35770346 10.1002/jmv.27968
37. Altindis M Puca E Shapo L Diagnosis of monkeypox virus—an overview Travel. Med. Infect. Dis. 2022 50 102459 10.1016/j.tmaid.2022.102459 36109000
Altindis, M., Puca, E. & Shapo, L. Diagnosis of monkeypox virus—an overview. Travel. Med. Infect. Dis. 50, 102459 (2022).36109000 10.1016/j.tmaid.2022.102459
38. Candela C Human Monkeypox experience in a tertiary level hospital in Milan, Italy, between May and October 2022: epidemiological features and clinical characteristics Viruses 2023 15 667 10.3390/v15030667 36992376
Candela, C. et al. Human Monkeypox experience in a tertiary level hospital in Milan, Italy, between May and October 2022: epidemiological features and clinical characteristics. Viruses 15, 667 (2023).36992376 10.3390/v15030667
39. Liu Q Clinical characteristics of Human Mpox (Monkeypox) in 2022: a systematic review and meta-analysis Pathogens 2023 12 146 10.3390/pathogens12010146 36678494
Liu, Q. et al. Clinical characteristics of Human Mpox (Monkeypox) in 2022: a systematic review and meta-analysis. Pathogens 12, 146 (2023).36678494 10.3390/pathogens12010146
40. Gaspari V Monkeypox outbreak 2022: clinical and virological features of 30 patients at the sexually transmitted diseases centre of Sant’ Orsola Hospital, Bologna, Northeastern Italy J. Clin. Microbiol. 2023 61 e0136522 10.1128/jcm.01365-22 36598196
Gaspari, V. et al. Monkeypox outbreak 2022: clinical and virological features of 30 patients at the sexually transmitted diseases centre of Sant’ Orsola Hospital, Bologna, Northeastern Italy. J. Clin. Microbiol. 61, e0136522 (2023).36598196 10.1128/jcm.01365-22
41. Shafaati M Zandi M State-of-the-art on monkeypox virus: an emerging zoonotic disease Infection 2022 50 1425 1430 10.1007/s15010-022-01935-3 36192607
Shafaati, M. & Zandi, M. State-of-the-art on monkeypox virus: an emerging zoonotic disease. Infection 50, 1425–1430 (2022).36192607 10.1007/s15010-022-01935-3
42. Kumar N Acharya A Gendelman HE Byrareddy SN The 2022 outbreak and the pathobiology of the monkeypox virus J. Autoimmun. 2022 131 102855 10.1016/j.jaut.2022.102855 35760647
Kumar, N., Acharya, A., Gendelman, H. E. & Byrareddy, S. N. The 2022 outbreak and the pathobiology of the monkeypox virus. J. Autoimmun. 131, 102855 (2022).35760647 10.1016/j.jaut.2022.102855
43. Alakunle E Moens U Nchinda G Okeke MI Monkeypox virus in Nigeria: infection biology, epidemiology, and evolution Viruses 2020 12 1257 10.3390/v12111257 33167496
Alakunle, E., Moens, U., Nchinda, G. & Okeke, M. I. Monkeypox virus in Nigeria: infection biology, epidemiology, and evolution. Viruses 12, 1257 (2020).33167496 10.3390/v12111257
44. Martínez-Fernández DE Human Monkeypox: a comprehensive overview of epidemiology, pathogenesis, diagnosis, treatment, and prevention strategies Pathogens 2023 12 947 10.3390/pathogens12070947 37513794
Martínez-Fernández, D. E. et al. Human Monkeypox: a comprehensive overview of epidemiology, pathogenesis, diagnosis, treatment, and prevention strategies. Pathogens 12, 947 (2023).37513794 10.3390/pathogens12070947
45. Malik S Monkeypox Virus: a comprehensive overview of viral pathology, immune response, and antiviral strategies Vaccines 2023 11 1345 10.3390/vaccines11081345 37631913
Malik, S. et al. Monkeypox Virus: a comprehensive overview of viral pathology, immune response, and antiviral strategies. Vaccines 11, 1345 (2023).37631913 10.3390/vaccines11081345
46. Zahmatyar M Human monkeypox: history, presentations, transmission, epidemiology, diagnosis, treatment, and prevention Front. Med. 2023 10 1157670 10.3389/fmed.2023.1157670
Zahmatyar, M. et al. Human monkeypox: history, presentations, transmission, epidemiology, diagnosis, treatment, and prevention. Front. Med. 10, 1157670 (2023).10.3389/fmed.2023.1157670
47. Srivastava S The Global Monkeypox (Mpox) outbreak: a comprehensive review Vaccines 2023 11 1093 10.3390/vaccines11061093 37376482
Srivastava, S. et al. The Global Monkeypox (Mpox) outbreak: a comprehensive review. Vaccines 11, 1093 (2023).37376482 10.3390/vaccines11061093
48. Fonti M Monkeypox associated acute arthritis Lancet Rheumatol. 2022 4 e804 10.1016/S2665-9913(22)00257-0 36247685
Fonti, M. et al. Monkeypox associated acute arthritis. Lancet Rheumatol. 4, e804 (2022).36247685 10.1016/S2665-9913(22)00257-0
49. Rao AK Interim clinical treatment considerations for severe manifestations of Mpox - United States, February 2023 Morb. Mortal. Wkly Rep. 2023 72 232 243 10.15585/mmwr.mm7209a4
Rao, A. K. et al. Interim clinical treatment considerations for severe manifestations of Mpox - United States, February 2023. Morb. Mortal. Wkly Rep. 72, 232–243 (2023).10.15585/mmwr.mm7209a4
50. Maqbool KU Cardiovascular manifestations of human Monkeypox virus: an updated review Curr. Probl. Cardiol. 2023 48 101869 10.1016/j.cpcardiol.2023.101869 37302648
Maqbool, K. U. et al. Cardiovascular manifestations of human Monkeypox virus: an updated review. Curr. Probl. Cardiol. 48, 101869 (2023).37302648 10.1016/j.cpcardiol.2023.101869
51. Harris E Severe form of Mpox identified in patients with advanced HIV JAMA 2023 329 968 36884268
Harris, E. Severe form of Mpox identified in patients with advanced HIV. JAMA 329, 968 (2023).36884268
52. Laurenson-Schafer H Description of the first global outbreak of mpox: an analysis of global surveillance data Lancet Glob. Health 2023 11 e1012 e1023 10.1016/S2214-109X(23)00198-5 37349031
Laurenson-Schafer, H. et al. Description of the first global outbreak of mpox: an analysis of global surveillance data. Lancet Glob. Health 11, e1012–e1023 (2023).37349031 10.1016/S2214-109X(23)00198-5
53. Fink DL Clinical features and management of individuals admitted to hospital with monkeypox and associated complications across the UK: a retrospective cohort study Lancet Infect. Dis. 2023 23 589 597 10.1016/S1473-3099(22)00806-4 36566771
Fink, D. L. et al. Clinical features and management of individuals admitted to hospital with monkeypox and associated complications across the UK: a retrospective cohort study. Lancet Infect. Dis. 23, 589–597 (2023).36566771 10.1016/S1473-3099(22)00806-4
54. Huhn GD Clinical characteristics of human monkeypox, and risk factors for severe disease Clin. Infect. Dis. 2005 41 1742 1751 10.1086/498115 16288398
Huhn, G. D. et al. Clinical characteristics of human monkeypox, and risk factors for severe disease. Clin. Infect. Dis. 41, 1742–1751 (2005).16288398 10.1086/498115
55. Li H The evolving epidemiology of monkeypox virus Cytokine Growth Factor Rev. 2022 68 1 12 10.1016/j.cytogfr.2022.10.002 36244878
Li, H. et al. The evolving epidemiology of monkeypox virus. Cytokine Growth Factor Rev. 68, 1–12 (2022).36244878 10.1016/j.cytogfr.2022.10.002
56. Condit RC Moussatche N Traktman P In a nutshell: structure and assembly of the vaccinia virion Adv. Virus Res. 2006 66 31 124 10.1016/S0065-3527(06)66002-8 16877059
Condit, R. C., Moussatche, N. & Traktman, P. In a nutshell: structure and assembly of the vaccinia virion. Adv. Virus Res. 66, 31–124 (2006).16877059 10.1016/S0065-3527(06)66002-8
57. Shchelkunov SN Analysis of the monkeypox virus genome Virology 2002 297 172 194 10.1006/viro.2002.1446 12083817
Shchelkunov, S. N. et al. Analysis of the monkeypox virus genome. Virology 297, 172–194 (2002).12083817 10.1006/viro.2002.1446
58. Garon CF Barbosa E Moss B Visualization of an inverted terminal repetition in vaccinia virus DNA Proc. Natl. Acad. Sci. USA 1978 75 4863 4867 10.1073/pnas.75.10.4863 283397
Garon, C. F., Barbosa, E. & Moss, B. Visualization of an inverted terminal repetition in vaccinia virus DNA. Proc. Natl. Acad. Sci. USA 75, 4863–4867 (1978).283397 10.1073/pnas.75.10.4863
59. Wittek R Inverted terminal repeats in rabbit poxvirus and vaccinia virus DNA J. Virol. 1978 28 171 181 10.1128/jvi.28.1.171-181.1978 212601
Wittek, R. et al. Inverted terminal repeats in rabbit poxvirus and vaccinia virus DNA. J. Virol. 28, 171–181 (1978).212601 10.1128/jvi.28.1.171-181.1978
60. Shchelkunov SN Human monkeypox and smallpox viruses: genomic comparison FEBS Lett. 2001 509 66 70 10.1016/S0014-5793(01)03144-1 11734207
Shchelkunov, S. N. et al. Human monkeypox and smallpox viruses: genomic comparison. FEBS Lett. 509, 66–70 (2001).11734207 10.1016/S0014-5793(01)03144-1
61. Andrei G Snoeck R Differences in pathogenicity among the mpox virus clades: impact on drug discovery and vaccine development Trends Pharmacol. Sci. 2023 44 719 739 10.1016/j.tips.2023.08.003 37673695
Andrei, G. & Snoeck, R. Differences in pathogenicity among the mpox virus clades: impact on drug discovery and vaccine development. Trends Pharmacol. Sci. 44, 719–739 (2023).37673695 10.1016/j.tips.2023.08.003
62. Wang L Genomic annotation and molecular evolution of monkeypox virus outbreak in 2022 J. Med. Virol. 2023 95 e28036 10.1002/jmv.28036 35906185
Wang, L. et al. Genomic annotation and molecular evolution of monkeypox virus outbreak in 2022. J. Med. Virol. 95, e28036 (2023).35906185 10.1002/jmv.28036
63. Isidro J Phylogenomic characterization and signs of microevolution in the 2022 multi-country outbreak of monkeypox virus Nat. Med. 2022 28 1569 1572 10.1038/s41591-022-01907-y 35750157
Isidro, J. et al. Phylogenomic characterization and signs of microevolution in the 2022 multi-country outbreak of monkeypox virus. Nat. Med. 28, 1569–1572 (2022).35750157 10.1038/s41591-022-01907-y
64. Armstrong JA Metz DH Young MR The mode of entry of vaccinia virus into L cells J. Gen. Virol. 1973 21 533 537 10.1099/0022-1317-21-3-533 4128637
Armstrong, J. A., Metz, D. H. & Young, M. R. The mode of entry of vaccinia virus into L cells. J. Gen. Virol. 21, 533–537 (1973).4128637 10.1099/0022-1317-21-3-533
65. Dales S The uptake and development of vaccinia virus in strain L cells followed with labeled viral deoxyribonucleic acid J. Cell Biol. 1963 18 51 72 10.1083/jcb.18.1.51 14024720
Dales, S. The uptake and development of vaccinia virus in strain L cells followed with labeled viral deoxyribonucleic acid. J. Cell Biol. 18, 51–72 (1963).14024720 10.1083/jcb.18.1.51
66. Haller SL Peng C McFadden G Rothenburg S Poxviruses and the evolution of host range and virulence Infect. Genet. Evol. 2014 21 15 40 10.1016/j.meegid.2013.10.014 24161410
Haller, S. L., Peng, C., McFadden, G. & Rothenburg, S. Poxviruses and the evolution of host range and virulence. Infect. Genet. Evol. 21, 15–40 (2014).24161410 10.1016/j.meegid.2013.10.014
67. Locker JK Entry of the two infectious forms of vaccinia virus at the plasma membane is signaling-dependent for the IMV but not the EEV Mol. Biol. Cell 2000 11 2497 2511 10.1091/mbc.11.7.2497 10888684
Locker, J. K. et al. Entry of the two infectious forms of vaccinia virus at the plasma membane is signaling-dependent for the IMV but not the EEV. Mol. Biol. Cell 11, 2497–2511 (2000).10888684 10.1091/mbc.11.7.2497
68. Schmidt FI Bleck CK Helenius A Mercer J Vaccinia extracellular virions enter cells by macropinocytosis and acid-activated membrane rupture EMBO J. 2011 30 3647 3661 10.1038/emboj.2011.245 21792173
Schmidt, F. I., Bleck, C. K., Helenius, A. & Mercer, J. Vaccinia extracellular virions enter cells by macropinocytosis and acid-activated membrane rupture. EMBO J. 30, 3647–3661 (2011).21792173 10.1038/emboj.2011.245
69. Doms RW Blumenthal R Moss B Fusion of intra- and extracellular forms of vaccinia virus with the cell membrane J. Virol. 1990 64 4884 4892 10.1128/jvi.64.10.4884-4892.1990 2398531
Doms, R. W., Blumenthal, R. & Moss, B. Fusion of intra- and extracellular forms of vaccinia virus with the cell membrane. J. Virol. 64, 4884–4892 (1990).2398531 10.1128/jvi.64.10.4884-4892.1990
70. Moss B Membrane fusion during poxvirus entry Semin. Cell Dev. Biol. 2016 60 89 96 10.1016/j.semcdb.2016.07.015 27423915
Moss, B. Membrane fusion during poxvirus entry. Semin. Cell Dev. Biol. 60, 89–96 (2016).27423915 10.1016/j.semcdb.2016.07.015
71. Chang A Metz DH Further investigations on the mode of entry of vaccinia virus into cells J. Gen. Virol. 1976 32 275 282 10.1099/0022-1317-32-2-275 798024
Chang, A. & Metz, D. H. Further investigations on the mode of entry of vaccinia virus into cells. J. Gen. Virol. 32, 275–282 (1976).798024 10.1099/0022-1317-32-2-275
72. Janeczko RA Rodriguez JF Esteban M Studies on the mechanism of entry of vaccinia virus in animal cells Arch. Virol. 1987 92 135 150 10.1007/BF01310068 3800657
Janeczko, R. A., Rodriguez, J. F. & Esteban, M. Studies on the mechanism of entry of vaccinia virus in animal cells. Arch. Virol. 92, 135–150 (1987).3800657 10.1007/BF01310068
73. Vanderplasschen A Hollinshead M Smith GL Intracellular and extracellular vaccinia virions enter cells by different mechanisms J. Gen. Virol. 1998 79 877 887 10.1099/0022-1317-79-4-877 9568984
Vanderplasschen, A., Hollinshead, M. & Smith, G. L. Intracellular and extracellular vaccinia virions enter cells by different mechanisms. J. Gen. Virol. 79, 877–887 (1998).9568984 10.1099/0022-1317-79-4-877
74. Ichihashi Y Extracellular enveloped vaccinia virus escapes neutralization Virology 1996 217 478 485 10.1006/viro.1996.0142 8610439
Ichihashi, Y. Extracellular enveloped vaccinia virus escapes neutralization. Virology 217, 478–485 (1996).8610439 10.1006/viro.1996.0142
75. Law M Smith GL Antibody neutralization of the extracellular enveloped form of vaccinia virus Virology 2001 280 132 142 10.1006/viro.2000.0750 11162827
Law, M. & Smith, G. L. Antibody neutralization of the extracellular enveloped form of vaccinia virus. Virology 280, 132–142 (2001).11162827 10.1006/viro.2000.0750
76. Vanderplasschen A Smith GL A novel virus binding assay using confocal microscopy: demonstration that the intracellular and extracellular vaccinia virions bind to different cellular receptors J. Virol. 1997 71 4032 4041 10.1128/jvi.71.5.4032-4041.1997 9094681
Vanderplasschen, A. & Smith, G. L. A novel virus binding assay using confocal microscopy: demonstration that the intracellular and extracellular vaccinia virions bind to different cellular receptors. J. Virol. 71, 4032–4041 (1997).9094681 10.1128/jvi.71.5.4032-4041.1997
77. Simons K Toomre D Lipid rafts and signal transduction Nat. Rev. Mol. Cell Biol. 2000 1 31 39 10.1038/35036052 11413487
Simons, K. & Toomre, D. Lipid rafts and signal transduction. Nat. Rev. Mol. Cell Biol. 1, 31–39 (2000).11413487 10.1038/35036052
78. Gee YJ Sea YL Lal SK Viral modulation of lipid rafts and their potential as putative antiviral targets Rev. Med. Virol. 2023 33 e2413 10.1002/rmv.2413 36504273
Gee, Y. J., Sea, Y. L. & Lal, S. K. Viral modulation of lipid rafts and their potential as putative antiviral targets. Rev. Med. Virol. 33, e2413 (2023).36504273 10.1002/rmv.2413
79. Peruzzu D Fecchi K Venturi G Gagliardi MC Repurposing amphotericin B and its liposomal formulation for the treatment of human Mpox Int. J. Mol. Sci. 2023 24 8896 10.3390/ijms24108896 37240241
Peruzzu, D., Fecchi, K., Venturi, G. & Gagliardi, M. C. Repurposing amphotericin B and its liposomal formulation for the treatment of human Mpox. Int. J. Mol. Sci. 24, 8896 (2023).37240241 10.3390/ijms24108896
80. Sekaran S Sekar SKR Repurposing cholesterol lowering drugs in the treatment and management of monkeypox Int. J. Surg. 2023 109 60 61 10.1097/JS9.0000000000000010 36799796
Sekaran, S. & Sekar, S. K. R. Repurposing cholesterol lowering drugs in the treatment and management of monkeypox. Int. J. Surg. 109, 60–61 (2023).36799796 10.1097/JS9.0000000000000010
81. He P SPR sensor-based analysis of the inhibition of marine sulfated glycans on interactions between Monkeypox virus proteins and glycosaminoglycans Mar. Drugs 2023 21 264 10.3390/md21050264 37233458
He, P. et al. SPR sensor-based analysis of the inhibition of marine sulfated glycans on interactions between Monkeypox virus proteins and glycosaminoglycans. Mar. Drugs 21, 264 (2023).37233458 10.3390/md21050264
82. Li M Three neutralizing mAbs induced by MPXV A29L protein recognizing different epitopes act synergistically against orthopoxvirus Emerg. Microbes. Infect. 2023 12 2223669 10.1080/22221751.2023.2223669 37288876
Li, M. et al. Three neutralizing mAbs induced by MPXV A29L protein recognizing different epitopes act synergistically against orthopoxvirus. Emerg. Microbes. Infect. 12, 2223669 (2023).37288876 10.1080/22221751.2023.2223669
83. Mallardo M Schleich S Krijnse Locker J Microtubule-dependent organization of vaccinia virus core-derived early mRNAs into distinct cytoplasmic structures Mol. Biol. Cell 2001 12 3875 3891 10.1091/mbc.12.12.3875 11739787
Mallardo, M., Schleich, S. & Krijnse Locker, J. Microtubule-dependent organization of vaccinia virus core-derived early mRNAs into distinct cytoplasmic structures. Mol. Biol. Cell 12, 3875–3891 (2001).11739787 10.1091/mbc.12.12.3875
84. Mercer J RNAi screening reveals proteasome- and Cullin3-dependent stages in vaccinia virus infection Cell Rep. 2012 2 1036 1047 10.1016/j.celrep.2012.09.003 23084750
Mercer, J. et al. RNAi screening reveals proteasome- and Cullin3-dependent stages in vaccinia virus infection. Cell Rep. 2, 1036–1047 (2012).23084750 10.1016/j.celrep.2012.09.003
85. Satheshkumar PS Anton LC Sanz P Moss B Inhibition of the ubiquitin-proteasome system prevents vaccinia virus DNA replication and expression of intermediate and late genes J. Virol. 2009 83 2469 2479 10.1128/JVI.01986-08 19129442
Satheshkumar, P. S., Anton, L. C., Sanz, P. & Moss, B. Inhibition of the ubiquitin-proteasome system prevents vaccinia virus DNA replication and expression of intermediate and late genes. J. Virol. 83, 2469–2479 (2009).19129442 10.1128/JVI.01986-08
86. Lant S Maluquer de Motes C Poxvirus interactions with the host ubiquitin system Pathogens 2021 10 1034 10.3390/pathogens10081034 34451498
Lant, S. & Maluquer de Motes, C. Poxvirus interactions with the host ubiquitin system. Pathogens 10, 1034 (2021).34451498 10.3390/pathogens10081034
87. Kates J Beeson J Ribonucleic acid synthesis in vaccinia virus. I. The mechanism of synthesis and release of RNA in vaccinia cores J. Mol. Biol. 1970 50 1 18 10.1016/0022-2836(70)90100-2 5453356
Kates, J. & Beeson, J. Ribonucleic acid synthesis in vaccinia virus. I. The mechanism of synthesis and release of RNA in vaccinia cores. J. Mol. Biol. 50, 1–18 (1970).5453356 10.1016/0022-2836(70)90100-2
88. Mallardo M Relationship between vaccinia virus intracellular cores, early mRNAs, and DNA replication sites J. Virol. 2002 76 5167 5183 10.1128/JVI.76.10.5167-5183.2002 11967332
Mallardo, M. et al. Relationship between vaccinia virus intracellular cores, early mRNAs, and DNA replication sites. J. Virol. 76, 5167–5183 (2002).11967332 10.1128/JVI.76.10.5167-5183.2002
89. Katsafanas GC Moss B Colocalization of transcription and translation within cytoplasmic poxvirus factories coordinates viral expression and subjugates host functions Cell Host Microbe 2007 2 221 228 10.1016/j.chom.2007.08.005 18005740
Katsafanas, G. C. & Moss, B. Colocalization of transcription and translation within cytoplasmic poxvirus factories coordinates viral expression and subjugates host functions. Cell Host Microbe 2, 221–228 (2007).18005740 10.1016/j.chom.2007.08.005
90. Kieser Q Cytoplasmic factories, virus assembly, and DNA replication kinetics collectively constrain the formation of poxvirus recombinants PLoS One 2020 15 e0228028 10.1371/journal.pone.0228028 31945138
Kieser, Q. et al. Cytoplasmic factories, virus assembly, and DNA replication kinetics collectively constrain the formation of poxvirus recombinants. PLoS One 15, e0228028 (2020).31945138 10.1371/journal.pone.0228028
91. Peng Q Structure of monkeypox virus DNA polymerase holoenzyme Science. 2023 379 100 105 10.1126/science.ade6360 36520947
Peng, Q. et al. Structure of monkeypox virus DNA polymerase holoenzyme. Science. 379, 100–105 (2023).36520947 10.1126/science.ade6360
92. Dsouza L Antiviral activities of two nucleos(t)ide analogs against vaccinia, Mpox, and cowpox viruses in primary human fibroblasts Antiviral Res. 2023 216 105651 10.1016/j.antiviral.2023.105651 37270160
Dsouza, L. et al. Antiviral activities of two nucleos(t)ide analogs against vaccinia, Mpox, and cowpox viruses in primary human fibroblasts. Antiviral Res. 216, 105651 (2023).37270160 10.1016/j.antiviral.2023.105651
93. Abdullah Al Awadh A Nucleotide and nucleoside-based drugs: past, present, and future Saudi J. Biol. Sci. 2022 29 103481 10.1016/j.sjbs.2022.103481 36389209
Abdullah Al Awadh, A. Nucleotide and nucleoside-based drugs: past, present, and future. Saudi J. Biol. Sci. 29, 103481 (2022).36389209 10.1016/j.sjbs.2022.103481
94. Johnson KA Dangerfield T Mechanisms of inhibition of viral RNA replication by nucleotide analogs Enzymes 2021 49 39 62 10.1016/bs.enz.2021.07.001 34696838
Johnson, K. A. & Dangerfield, T. Mechanisms of inhibition of viral RNA replication by nucleotide analogs. Enzymes 49, 39–62 (2021).34696838 10.1016/bs.enz.2021.07.001
95. Andrei G Snoeck R Cidofovir activity against poxvirus infections Viruses 2010 2 2803 2830 10.3390/v2122803 21994641
Andrei, G. & Snoeck, R. Cidofovir activity against poxvirus infections. Viruses 2, 2803–2830 (2010).21994641 10.3390/v2122803
96. Lebeau I Activities of alkoxyalkyl esters of cidofovir (CDV), cyclic CDV, and (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine against orthopoxviruses in cell monolayers and in organotypic cultures Antimicrob. Agents Chemother. 2006 50 2525 2529 10.1128/AAC.01489-05 16801436
Lebeau, I. et al. Activities of alkoxyalkyl esters of cidofovir (CDV), cyclic CDV, and (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine against orthopoxviruses in cell monolayers and in organotypic cultures. Antimicrob. Agents Chemother. 50, 2525–2529 (2006).16801436 10.1128/AAC.01489-05
97. Stittelaar KJ Antiviral treatment is more effective than smallpox vaccination upon lethal monkeypox virus infection Nature 2006 439 745 748 10.1038/nature04295 16341204
Stittelaar, K. J. et al. Antiviral treatment is more effective than smallpox vaccination upon lethal monkeypox virus infection. Nature 439, 745–748 (2006).16341204 10.1038/nature04295
98. Mailhe M Clinical characteristics of ambulatory and hospitalized patients with monkeypox virus infection: an observational cohort study Clin. Microbiol. Infect. 2023 29 233 239 10.1016/j.cmi.2022.08.012 36028090
Mailhe, M. et al. Clinical characteristics of ambulatory and hospitalized patients with monkeypox virus infection: an observational cohort study. Clin. Microbiol. Infect. 29, 233–239 (2023).36028090 10.1016/j.cmi.2022.08.012
99. Chenchula S A systematic review to identify novel clinical characteristics of monkeypox virus infection and therapeutic and preventive strategies to combat the virus Arch. Virol. 2023 168 195 10.1007/s00705-023-05808-4 37386209
Chenchula, S. et al. A systematic review to identify novel clinical characteristics of monkeypox virus infection and therapeutic and preventive strategies to combat the virus. Arch. Virol. 168, 195 (2023).37386209 10.1007/s00705-023-05808-4
100. Byrareddy SN Potential therapeutic targets for Mpox: the evidence to date Expert Opin. Ther. Targets 2023 27 419 431 10.1080/14728222.2023.2230361 37368464
Byrareddy, S. N. et al. Potential therapeutic targets for Mpox: the evidence to date. Expert Opin. Ther. Targets 27, 419–431 (2023).37368464 10.1080/14728222.2023.2230361
101. Shamim MA The use of antivirals in the treatment of human monkeypox outbreaks: a systematic review Int. J. Infect. Dis. 2023 127 150 161 10.1016/j.ijid.2022.11.040 36470502
Shamim, M. A. et al. The use of antivirals in the treatment of human monkeypox outbreaks: a systematic review. Int. J. Infect. Dis. 127, 150–161 (2023).36470502 10.1016/j.ijid.2022.11.040
102. Kim GH Jun JB Altered serum uric acid levels in kidney disorders Life 2022 12 1891 10.3390/life12111891 36431026
Kim, G. H. & Jun, J. B. Altered serum uric acid levels in kidney disorders. Life 12, 1891 (2022).36431026 10.3390/life12111891
103. Caetano-Pinto P Amplifying the impact of kidney microphysiological systems: predicting renal drug clearance using mechanistic modelling based on reconstructed drug secretion Altex 2022 40 408 424 36343109
Caetano-Pinto, P. et al. Amplifying the impact of kidney microphysiological systems: predicting renal drug clearance using mechanistic modelling based on reconstructed drug secretion. Altex 40, 408–424 (2022).36343109
104. Velioglu A Topical cidofovir-related acute kidney injury in a kidney transplant recipient Clin. Transplant. 2022 36 e14824 10.1111/ctr.14824 36117328
Velioglu, A. et al. Topical cidofovir-related acute kidney injury in a kidney transplant recipient. Clin. Transplant. 36, e14824 (2022).36117328 10.1111/ctr.14824
105. Imran M Oral brincidofovir therapy for monkeypox outbreak: a focused review on the therapeutic potential, clinical studies, patent literature, and prospects Biomedicines 2023 11 278 10.3390/biomedicines11020278 36830816
Imran, M. et al. Oral brincidofovir therapy for monkeypox outbreak: a focused review on the therapeutic potential, clinical studies, patent literature, and prospects. Biomedicines 11, 278 (2023).36830816 10.3390/biomedicines11020278
106. Shamim MA Pharmacological treatment and vaccines in monkeypox virus: a narrative review and bibliometric analysis Front. Pharmacol. 2023 14 1149909 10.3389/fphar.2023.1149909 37214444
Shamim, M. A. et al. Pharmacological treatment and vaccines in monkeypox virus: a narrative review and bibliometric analysis. Front. Pharmacol. 14, 1149909 (2023).37214444 10.3389/fphar.2023.1149909
107. Wang B Disulfide-incorporated lipid prodrugs of cidofovir: synthesis, antiviral activity, and release mechanism Eur. J. Med. Chem. 2023 258 115601 10.1016/j.ejmech.2023.115601 37390509
Wang, B. et al. Disulfide-incorporated lipid prodrugs of cidofovir: synthesis, antiviral activity, and release mechanism. Eur. J. Med. Chem. 258, 115601 (2023).37390509 10.1016/j.ejmech.2023.115601
108. Stabenow J A mouse model of lethal infection for evaluating prophylactics and therapeutics against Monkeypox virus J. Virol. 2010 84 3909 3920 10.1128/JVI.02012-09 20130052
Stabenow, J. et al. A mouse model of lethal infection for evaluating prophylactics and therapeutics against Monkeypox virus. J. Virol. 84, 3909–3920 (2010).20130052 10.1128/JVI.02012-09
109. Adler H Clinical features and management of human monkeypox: a retrospective observational study in the UK Lancet Infect. Dis. 2022 22 1153 1162 10.1016/S1473-3099(22)00228-6 35623380
Adler, H. et al. Clinical features and management of human monkeypox: a retrospective observational study in the UK. Lancet Infect. Dis. 22, 1153–1162 (2022).35623380 10.1016/S1473-3099(22)00228-6
110. Bojkova D Repurposing of the antibiotic nitroxoline for the treatment of mpox J. Med. Virol. 2023 95 e28652 10.1002/jmv.28652 36897017
Bojkova, D. et al. Repurposing of the antibiotic nitroxoline for the treatment of mpox. J. Med. Virol. 95, e28652 (2023).36897017 10.1002/jmv.28652
111. Eriksson U Serine peptide phosphoester prodrugs of cyclic cidofovir: synthesis, transport, and antiviral activity Mol. Pharm. 2008 5 598 609 10.1021/mp8000099 18481868
Eriksson, U. et al. Serine peptide phosphoester prodrugs of cyclic cidofovir: synthesis, transport, and antiviral activity. Mol. Pharm. 5, 598–609 (2008).18481868 10.1021/mp8000099
112. Peterson LW Synthesis, transport and antiviral activity of Ala-Ser and Val-Ser prodrugs of cidofovir Bioorg. Med. Chem. Lett. 2011 21 4045 4049 10.1016/j.bmcl.2011.04.126 21641218
Peterson, L. W. et al. Synthesis, transport and antiviral activity of Ala-Ser and Val-Ser prodrugs of cidofovir. Bioorg. Med. Chem. Lett. 21, 4045–4049 (2011).21641218 10.1016/j.bmcl.2011.04.126
113. Lipka E NPP-669, a novel broad-spectrum antiviral therapeutic with excellent cellular uptake, antiviral potency, oral bioavailability, preclinical efficacy, and a promising safety margin Mol. Pharm. 2023 20 370 382 10.1021/acs.molpharmaceut.2c00668 36484496
Lipka, E. et al. NPP-669, a novel broad-spectrum antiviral therapeutic with excellent cellular uptake, antiviral potency, oral bioavailability, preclinical efficacy, and a promising safety margin. Mol. Pharm. 20, 370–382 (2023).36484496 10.1021/acs.molpharmaceut.2c00668
114. Baker RO Bray M Huggins JW Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections Antiviral Res. 2003 57 13 23 10.1016/S0166-3542(02)00196-1 12615299
Baker, R. O., Bray, M. & Huggins, J. W. Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections. Antiviral Res. 57, 13–23 (2003).12615299 10.1016/S0166-3542(02)00196-1
115. Smee DF Bailey KW Sidwell RW Treatment of cowpox virus respiratory infections in mice with ribavirin as a single agent or followed sequentially by cidofovir Antivir. Chem. Chemother. 2000 11 303 309 10.1177/095632020001100406 10950392
Smee, D. F., Bailey, K. W. & Sidwell, R. W. Treatment of cowpox virus respiratory infections in mice with ribavirin as a single agent or followed sequentially by cidofovir. Antivir. Chem. Chemother. 11, 303–309 (2000).10950392 10.1177/095632020001100406
116. Kannan SR Mutations in the monkeypox virus replication complex: potential contributing factors to the 2022 outbreak J. Autoimmun. 2022 133 102928 10.1016/j.jaut.2022.102928 36252459
Kannan, S. R. et al. Mutations in the monkeypox virus replication complex: potential contributing factors to the 2022 outbreak. J. Autoimmun. 133, 102928 (2022).36252459 10.1016/j.jaut.2022.102928
117. Andrei G Cidofovir resistance in vaccinia virus is linked to diminished virulence in mice J. Virol. 2006 80 9391 9401 10.1128/JVI.00605-06 16973545
Andrei, G. et al. Cidofovir resistance in vaccinia virus is linked to diminished virulence in mice. J. Virol. 80, 9391–9401 (2006).16973545 10.1128/JVI.00605-06
118. Kornbluth RS Mutations in the E9L polymerase gene of cidofovir-resistant vaccinia virus strain WR are associated with the drug resistance phenotype Antimicrob. Agents Chemother. 2006 50 4038 4043 10.1128/AAC.00380-06 16982794
Kornbluth, R. S. et al. Mutations in the E9L polymerase gene of cidofovir-resistant vaccinia virus strain WR are associated with the drug resistance phenotype. Antimicrob. Agents Chemother. 50, 4038–4043 (2006).16982794 10.1128/AAC.00380-06
119. Duraffour S KAY-2-41, a novel nucleoside analogue inhibitor of orthopoxviruses in vitro and in vivo Antimicrob. Agents Chemother. 2014 58 27 37 10.1128/AAC.01601-13 24126587
Duraffour, S. et al. KAY-2-41, a novel nucleoside analogue inhibitor of orthopoxviruses in vitro and in vivo. Antimicrob. Agents Chemother. 58, 27–37 (2014).24126587 10.1128/AAC.01601-13
120. Coen N Antiherpesvirus activities of two novel 4’-thiothymidine derivatives, KAY-2-41 and KAH-39-149, are dependent on viral and cellular thymidine kinases Antimicrob. Agents Chemother. 2014 58 4328 4340 10.1128/AAC.02825-14 24820089
Coen, N. et al. Antiherpesvirus activities of two novel 4’-thiothymidine derivatives, KAY-2-41 and KAH-39-149, are dependent on viral and cellular thymidine kinases. Antimicrob. Agents Chemother. 58, 4328–4340 (2014).24820089 10.1128/AAC.02825-14
121. Altayb HN Fludarabine, a potential DNA-dependent RNA polymerase inhibitor, as a prospective drug against Monkeypox virus: a computational approach Pharmaceuticals 2022 15 1129 10.3390/ph15091129 36145351
Altayb, H. N. Fludarabine, a potential DNA-dependent RNA polymerase inhibitor, as a prospective drug against Monkeypox virus: a computational approach. Pharmaceuticals 15, 1129 (2022).36145351 10.3390/ph15091129
122. Dutt M Drug repurposing for Mpox: discovery of small molecules as potential inhibitors against DNA-dependent RNA polymerase using molecular modeling approach J. Cell Biochem. 2023 124 701 715 10.1002/jcb.30397 36946432
Dutt, M. et al. Drug repurposing for Mpox: discovery of small molecules as potential inhibitors against DNA-dependent RNA polymerase using molecular modeling approach. J. Cell Biochem. 124, 701–715 (2023).36946432 10.1002/jcb.30397
123. Abduljalil JM Elfiky AA Elgohary AM Exploration of natural compounds against the human mpox virus DNA-dependent RNA polymerase in silico J. Infect. Public Health 2023 16 996 1003 10.1016/j.jiph.2023.04.019 37167647
Abduljalil, J. M., Elfiky, A. A. & Elgohary, A. M. Exploration of natural compounds against the human mpox virus DNA-dependent RNA polymerase in silico. J. Infect. Public Health 16, 996–1003 (2023).37167647 10.1016/j.jiph.2023.04.019
124. Tolonen N Doglio L Schleich S Krijnse Locker J Vaccinia virus DNA replication occurs in endoplasmic reticulum-enclosed cytoplasmic mini-nuclei Mol. Biol. Cell 2001 12 2031 2046 10.1091/mbc.12.7.2031 11452001
Tolonen, N., Doglio, L., Schleich, S. & Krijnse Locker, J. Vaccinia virus DNA replication occurs in endoplasmic reticulum-enclosed cytoplasmic mini-nuclei. Mol. Biol. Cell 12, 2031–2046 (2001).11452001 10.1091/mbc.12.7.2031
125. Maruri-Avidal L Weisberg AS Moss B Direct formation of vaccinia virus membranes from the endoplasmic reticulum in the absence of the newly characterized L2-interacting protein A30.5 J. Virol. 2013 87 12313 12326 10.1128/JVI.02137-13 24027302
Maruri-Avidal, L., Weisberg, A. S. & Moss, B. Direct formation of vaccinia virus membranes from the endoplasmic reticulum in the absence of the newly characterized L2-interacting protein A30.5. J. Virol. 87, 12313–12326 (2013).24027302 10.1128/JVI.02137-13
126. Liu L Cooper T Howley PM Hayball JD From crescent to mature virion: vaccinia virus assembly and maturation Viruses. 2014 6 3787 3808 10.3390/v6103787 25296112
Liu, L., Cooper, T., Howley, P. M. & Hayball, J. D. From crescent to mature virion: vaccinia virus assembly and maturation. Viruses. 6, 3787–3808 (2014).25296112 10.3390/v6103787
127. Greseth MD Traktman P The life cycle of the vaccinia virus genome Annu. Rev. Virol. 2022 9 239 259 10.1146/annurev-virology-091919-104752 35584888
Greseth, M. D. & Traktman, P. The life cycle of the vaccinia virus genome. Annu. Rev. Virol. 9, 239–259 (2022).35584888 10.1146/annurev-virology-091919-104752
128. Tooze J Progeny vaccinia and human cytomegalovirus particles utilize early endosomal cisternae for their envelopes Eur. J. Cell Biol. 1993 60 163 178 8385018
Tooze, J. et al. Progeny vaccinia and human cytomegalovirus particles utilize early endosomal cisternae for their envelopes. Eur. J. Cell Biol. 60, 163–178 (1993).8385018
129. Alzhanova D Hruby DE A trans-Golgi network resident protein, golgin-97, accumulates in viral factories and incorporates into virions during poxvirus infection J. Virol. 2006 80 11520 11527 10.1128/JVI.00287-06 16987983
Alzhanova, D. & Hruby, D. E. A trans-Golgi network resident protein, golgin-97, accumulates in viral factories and incorporates into virions during poxvirus infection. J. Virol. 80, 11520–11527 (2006).16987983 10.1128/JVI.00287-06
130. Sodeik B Assembly of vaccinia virus: role of the intermediate compartment between the endoplasmic reticulum and the Golgi stacks J. Cell Biol. 1993 121 521 541 10.1083/jcb.121.3.521 8486734
Sodeik, B. et al. Assembly of vaccinia virus: role of the intermediate compartment between the endoplasmic reticulum and the Golgi stacks. J. Cell Biol. 121, 521–541 (1993).8486734 10.1083/jcb.121.3.521
131. Schmelz M Assembly of vaccinia virus: the second wrapping cisterna is derived from the trans Golgi network J. Virol. 1994 68 130 147 10.1128/jvi.68.1.130-147.1994 8254722
Schmelz, M. et al. Assembly of vaccinia virus: the second wrapping cisterna is derived from the trans Golgi network. J. Virol. 68, 130–147 (1994).8254722 10.1128/jvi.68.1.130-147.1994
132. Sivan G Weisberg AS Americo JL Moss B Retrograde transport from early endosomes to the trans-Golgi network enables membrane wrapping and egress of vaccinia virus virions J. Virol. 2016 90 8891 8905 10.1128/JVI.01114-16 27466413
Sivan, G., Weisberg, A. S., Americo, J. L. & Moss, B. Retrograde transport from early endosomes to the trans-Golgi network enables membrane wrapping and egress of vaccinia virus virions. J. Virol. 90, 8891–8905 (2016).27466413 10.1128/JVI.01114-16
133. Bonifacino JS Rojas R Retrograde transport from endosomes to the trans-Golgi network Nat. Rev. Mol. Cell Biol. 2006 7 568 579 10.1038/nrm1985 16936697
Bonifacino, J. S. & Rojas, R. Retrograde transport from endosomes to the trans-Golgi network. Nat. Rev. Mol. Cell Biol. 7, 568–579 (2006).16936697 10.1038/nrm1985
134. Blasco R Moss B Role of cell-associated enveloped vaccinia virus in cell-to-cell spread J. Virol. 1992 66 4170 4179 10.1128/jvi.66.7.4170-4179.1992 1602540
Blasco, R. & Moss, B. Role of cell-associated enveloped vaccinia virus in cell-to-cell spread. J. Virol. 66, 4170–4179 (1992).1602540 10.1128/jvi.66.7.4170-4179.1992
135. Smith GL Law M The exit of vaccinia virus from infected cells Virus Res. 2004 106 189 197 10.1016/j.virusres.2004.08.015 15567497
Smith, G. L. & Law, M. The exit of vaccinia virus from infected cells. Virus Res. 106, 189–197 (2004).15567497 10.1016/j.virusres.2004.08.015
136. Roper RL Wolffe EJ Weisberg A Moss B The envelope protein encoded by the A33R gene is required for formation of actin-containing microvilli and efficient cell-to-cell spread of vaccinia virus J. Virol. 1998 72 4192 4204 10.1128/JVI.72.5.4192-4204.1998 9557708
Roper, R. L., Wolffe, E. J., Weisberg, A. & Moss, B. The envelope protein encoded by the A33R gene is required for formation of actin-containing microvilli and efficient cell-to-cell spread of vaccinia virus. J. Virol. 72, 4192–4204 (1998).9557708 10.1128/JVI.72.5.4192-4204.1998
137. Roberts KL Smith GL Vaccinia virus morphogenesis and dissemination Trends Microbiol. 2008 16 472 479 10.1016/j.tim.2008.07.009 18789694
Roberts, K. L. & Smith, G. L. Vaccinia virus morphogenesis and dissemination. Trends Microbiol. 16, 472–479 (2008).18789694 10.1016/j.tim.2008.07.009
138. Arakawa Y The release of vaccinia virus from infected cells requires RhoA-mDia modulation of cortical actin Cell Host Microbe 2007 1 227 240 10.1016/j.chom.2007.04.006 18005701
Arakawa, Y. et al. The release of vaccinia virus from infected cells requires RhoA-mDia modulation of cortical actin. Cell Host Microbe 1, 227–240 (2007).18005701 10.1016/j.chom.2007.04.006
139. Martinez-Quiles N WIP regulates N-WASP-mediated actin polymerization and filopodium formation Nat. Cell Biol. 2001 3 484 491 10.1038/35074551 11331876
Martinez-Quiles, N. et al. WIP regulates N-WASP-mediated actin polymerization and filopodium formation. Nat. Cell Biol. 3, 484–491 (2001).11331876 10.1038/35074551
140. Frischknecht F Actin-based motility of vaccinia virus mimics receptor tyrosine kinase signalling Nature 1999 401 926 929 10.1038/44860 10553910
Frischknecht, F. et al. Actin-based motility of vaccinia virus mimics receptor tyrosine kinase signalling. Nature 401, 926–929 (1999).10553910 10.1038/44860
141. Masters J Poxvirus infection rapidly activates tyrosine kinase signal transduction J. Biol. Chem. 2001 276 48371 48375 10.1074/jbc.M108019200 11591716
Masters, J. et al. Poxvirus infection rapidly activates tyrosine kinase signal transduction. J. Biol. Chem. 276, 48371–48375 (2001).11591716 10.1074/jbc.M108019200
142. Ward BM Pox, dyes, and videotape: making movies of GFP-labeled vaccinia virus Methods Mol. Biol. 2004 269 205 218 15114018
Ward, B. M. Pox, dyes, and videotape: making movies of GFP-labeled vaccinia virus. Methods Mol. Biol. 269, 205–218 (2004).15114018
143. Cudmore S Cossart P Griffiths G Way M Actin-based motility of vaccinia virus Nature 1995 378 636 638 10.1038/378636a0 8524400
Cudmore, S., Cossart, P., Griffiths, G. & Way, M. Actin-based motility of vaccinia virus. Nature 378, 636–638 (1995).8524400 10.1038/378636a0
144. Hollinshead M Vaccinia virus utilizes microtubules for movement to the cell surface J. Cell Biol. 2001 154 389 402 10.1083/jcb.200104124 11470826
Hollinshead, M. et al. Vaccinia virus utilizes microtubules for movement to the cell surface. J. Cell Biol. 154, 389–402 (2001).11470826 10.1083/jcb.200104124
145. Geada MM Movements of vaccinia virus intracellular enveloped virions with GFP tagged to the F13L envelope protein J. Gen. Virol. 2001 82 2747 2760 10.1099/0022-1317-82-11-2747 11602786
Geada, M. M. et al. Movements of vaccinia virus intracellular enveloped virions with GFP tagged to the F13L envelope protein. J. Gen. Virol. 82, 2747–2760 (2001).11602786 10.1099/0022-1317-82-11-2747
146. Ward BM Moss B Visualization of intracellular movement of vaccinia virus virions containing a green fluorescent protein-B5R membrane protein chimera J. Virol. 2001 75 4802 4813 10.1128/JVI.75.10.4802-4813.2001 11312352
Ward, B. M. & Moss, B. Visualization of intracellular movement of vaccinia virus virions containing a green fluorescent protein-B5R membrane protein chimera. J. Virol. 75, 4802–4813 (2001).11312352 10.1128/JVI.75.10.4802-4813.2001
147. Ward BM Moss B Vaccinia virus intracellular movement is associated with microtubules and independent of actin tails J. Virol. 2001 75 11651 11663 10.1128/JVI.75.23.11651-11663.2001 11689647
Ward, B. M. & Moss, B. Vaccinia virus intracellular movement is associated with microtubules and independent of actin tails. J. Virol. 75, 11651–11663 (2001).11689647 10.1128/JVI.75.23.11651-11663.2001
148. Reeves PM Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases Nat. Med. 2005 11 731 739 10.1038/nm1265 15980865
Reeves, P. M. et al. Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nat. Med. 11, 731–739 (2005).15980865 10.1038/nm1265
149. Priyamvada L Discovery of Retro-1 analogs exhibiting enhanced anti-vaccinia virus activity Front. Microbiol. 2020 11 603 10.3389/fmicb.2020.00603 32390964
Priyamvada, L. et al. Discovery of Retro-1 analogs exhibiting enhanced anti-vaccinia virus activity. Front. Microbiol. 11, 603 (2020).32390964 10.3389/fmicb.2020.00603
150. Eppstein DA Epidermal growth factor receptor occupancy inhibits vaccinia virus infection Nature 1985 318 663 665 10.1038/318663a0 3001528
Eppstein, D. A. et al. Epidermal growth factor receptor occupancy inhibits vaccinia virus infection. Nature 318, 663–665 (1985).3001528 10.1038/318663a0
151. Carlin CR Role of EGF receptor regulatory networks in the host response to viral infections Front. Cell. Infect. Microbiol. 2021 11 820355 10.3389/fcimb.2021.820355 35083168
Carlin, C. R. Role of EGF receptor regulatory networks in the host response to viral infections. Front. Cell. Infect. Microbiol. 11, 820355 (2021).35083168 10.3389/fcimb.2021.820355
152. Yang H Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction J. Clin. Investig. 2005 115 379 387 10.1172/JCI200523220 15690085
Yang, H. et al. Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction. J. Clin. Investig. 115, 379–387 (2005).15690085 10.1172/JCI200523220
153. Beerli C Vaccinia virus hijacks EGFR signalling to enhance virus spread through rapid and directed infected cell motility Nat. Microbiol. 2019 4 216 225 10.1038/s41564-018-0288-2 30420785
Beerli, C. et al. Vaccinia virus hijacks EGFR signalling to enhance virus spread through rapid and directed infected cell motility. Nat. Microbiol. 4, 216–225 (2019).30420785 10.1038/s41564-018-0288-2
154. Lai KM Lee WL The roles of epidermal growth factor receptor in viral infections Growth Factors 2022 40 46 72 10.1080/08977194.2022.2063123 35439043
Lai, K. M. & Lee, W. L. The roles of epidermal growth factor receptor in viral infections. Growth Factors 40, 46–72 (2022).35439043 10.1080/08977194.2022.2063123
155. Langhammer S Koban R Yue C Ellerbrok H Inhibition of poxvirus spreading by the anti-tumor drug Gefitinib (Iressa) Antiviral Res. 2011 89 64 70 10.1016/j.antiviral.2010.11.006 21094187
Langhammer, S., Koban, R., Yue, C. & Ellerbrok, H. Inhibition of poxvirus spreading by the anti-tumor drug Gefitinib (Iressa). Antiviral Res. 89, 64–70 (2011).21094187 10.1016/j.antiviral.2010.11.006
156. Wolffe EJ Weisberg AS Moss B Role for the vaccinia virus A36R outer envelope protein in the formation of virus-tipped actin-containing microvilli and cell-to-cell virus spread Virology 1998 244 20 26 10.1006/viro.1998.9103 9581774
Wolffe, E. J., Weisberg, A. S. & Moss, B. Role for the vaccinia virus A36R outer envelope protein in the formation of virus-tipped actin-containing microvilli and cell-to-cell virus spread. Virology 244, 20–26 (1998).9581774 10.1006/viro.1998.9103
157. Miah MM Tabassum N Afroj Zinnia M Islam A Drug and anti-viral peptide design to inhibit the monkeypox virus by restricting A36R protein Bioinform. Biol. Insights 2022 16 11779322221141164 10.1177/11779322221141164 36570327
Miah, M. M., Tabassum, N., Afroj Zinnia, M. & Islam, A. Drug and anti-viral peptide design to inhibit the monkeypox virus by restricting A36R protein. Bioinform. Biol. Insights 16, 11779322221141164 (2022).36570327 10.1177/11779322221141164
158. McIntosh AA Smith GL Vaccinia virus glycoprotein A34R is required for infectivity of extracellular enveloped virus J. Virol. 1996 70 272 281 10.1128/jvi.70.1.272-281.1996 8523536
McIntosh, A. A. & Smith, G. L. Vaccinia virus glycoprotein A34R is required for infectivity of extracellular enveloped virus. J. Virol. 70, 272–281 (1996).8523536 10.1128/jvi.70.1.272-281.1996
159. Herrera E Lorenzo MM Blasco R Isaacs SN Functional analysis of vaccinia virus B5R protein: essential role in virus envelopment is independent of a large portion of the extracellular domain J. Virol. 1998 72 294 302 10.1128/JVI.72.1.294-302.1998 9420227
Herrera, E., Lorenzo, M. M., Blasco, R. & Isaacs, S. N. Functional analysis of vaccinia virus B5R protein: essential role in virus envelopment is independent of a large portion of the extracellular domain. J. Virol. 72, 294–302 (1998).9420227 10.1128/JVI.72.1.294-302.1998
160. Blasco R Moss B Extracellular vaccinia virus formation and cell-to-cell virus transmission are prevented by deletion of the gene encoding the 37,000-Dalton outer envelope protein J. Virol. 1991 65 5910 5920 10.1128/jvi.65.11.5910-5920.1991 1920620
Blasco, R. & Moss, B. Extracellular vaccinia virus formation and cell-to-cell virus transmission are prevented by deletion of the gene encoding the 37,000-Dalton outer envelope protein. J. Virol. 65, 5910–5920 (1991).1920620 10.1128/jvi.65.11.5910-5920.1991
161. Bryk P Brewer MG Ward BM Vaccinia virus phospholipase protein F13 promotes rapid entry of extracellular virions into cells J. Virol. 2018 92 e02145 17 10.1128/JVI.02154-17 29491158
Bryk, P., Brewer, M. G. & Ward, B. M. Vaccinia virus phospholipase protein F13 promotes rapid entry of extracellular virions into cells. J. Virol. 92, e02145–17 (2018).29491158 10.1128/JVI.02154-17
162. Schmutz C Payne LG Gubser J Wittek R A mutation in the gene encoding the vaccinia virus 37,000-M(r) protein confers resistance to an inhibitor of virus envelopment and release J. Virol. 1991 65 3435 3442 10.1128/jvi.65.7.3435-3442.1991 2041074
Schmutz, C., Payne, L. G., Gubser, J. & Wittek, R. A mutation in the gene encoding the vaccinia virus 37,000-M(r) protein confers resistance to an inhibitor of virus envelopment and release. J. Virol. 65, 3435–3442 (1991).2041074 10.1128/jvi.65.7.3435-3442.1991
163. Borrego B Lorenzo MM Blasco R Complementation of P37 (F13L gene) knock-out in vaccinia virus by a cell line expressing the gene constitutively J. Gen. Virol. 1999 80 425 432 10.1099/0022-1317-80-2-425 10073703
Borrego, B., Lorenzo, M. M. & Blasco, R. Complementation of P37 (F13L gene) knock-out in vaccinia virus by a cell line expressing the gene constitutively. J. Gen. Virol. 80, 425–432 (1999).10073703 10.1099/0022-1317-80-2-425
164. Merchlinsky M The development and approval of tecoviromat (TPOXX(®)), the first antiviral against smallpox Antiviral Res. 2019 168 168 174 10.1016/j.antiviral.2019.06.005 31181284
Merchlinsky, M. et al. The development and approval of tecoviromat (TPOXX(®)), the first antiviral against smallpox. Antiviral Res. 168, 168–174 (2019).31181284 10.1016/j.antiviral.2019.06.005
165. Warner BM In vitro and in vivo efficacy of tecovirimat against a recently emerged 2022 monkeypox virus isolate Sci. Transl. Med. 2022 14 eade7646 10.1126/scitranslmed.ade7646 36318038
Warner, B. M. et al. In vitro and in vivo efficacy of tecovirimat against a recently emerged 2022 monkeypox virus isolate. Sci. Transl. Med. 14, eade7646 (2022).36318038 10.1126/scitranslmed.ade7646
166. Russo AT Effects of treatment delay on efficacy of tecovirimat following lethal aerosol monkeypox virus challenge in cynomolgus macaques J. Infect. Dis. 2018 218 1490 1499 10.1093/infdis/jiy326 29982575
Russo, A. T. et al. Effects of treatment delay on efficacy of tecovirimat following lethal aerosol monkeypox virus challenge in cynomolgus macaques. J. Infect. Dis. 218, 1490–1499 (2018).29982575 10.1093/infdis/jiy326
167. O’Laughlin K Clinical use of tecovirimat (Tpoxx) for treatment of Monkeypox under an investigational new drug protocol—United States, May-August 2022 Morb. Mortal. Wkly Rep. 2022 71 1190 1195 10.15585/mmwr.mm7137e1
O’Laughlin, K. et al. Clinical use of tecovirimat (Tpoxx) for treatment of Monkeypox under an investigational new drug protocol—United States, May-August 2022. Morb. Mortal. Wkly Rep. 71, 1190–1195 (2022).10.15585/mmwr.mm7137e1
168. Das T Efficacy of smallpox approved tecovirimat (Tpoxx) drug against Monkeypox: current update and futuristic prospects Int. J. Surg. 2023 109 1528 1530 10.1097/JS9.0000000000000077 36974695
Das, T. et al. Efficacy of smallpox approved tecovirimat (Tpoxx) drug against Monkeypox: current update and futuristic prospects. Int. J. Surg. 109, 1528–1530 (2023).36974695 10.1097/JS9.0000000000000077
169. Li D Liu Y Li K Zhang L Targeting F13 from monkeypox virus and variola virus by tecovirimat: molecular simulation analysis J. Infect. 2022 85 e99 e101 10.1016/j.jinf.2022.07.001 35810941
Li, D., Liu, Y., Li, K. & Zhang, L. Targeting F13 from monkeypox virus and variola virus by tecovirimat: molecular simulation analysis. J. Infect. 85, e99–e101 (2022).35810941 10.1016/j.jinf.2022.07.001
170. Frenois-Veyrat G Tecovirimat is effective against human monkeypox virus in vitro at nanomolar concentrations Nat. Microbiol. 2022 7 1951 1955 10.1038/s41564-022-01269-8 36344621
Frenois-Veyrat, G. et al. Tecovirimat is effective against human monkeypox virus in vitro at nanomolar concentrations. Nat. Microbiol. 7, 1951–1955 (2022).36344621 10.1038/s41564-022-01269-8
171. McQuiston JH The CDC domestic Mpox response - United States, 2022-2023 Morb. Mortal. Wkly Rep. 2023 72 547 552 10.15585/mmwr.mm7220a2
McQuiston, J. H. et al. The CDC domestic Mpox response - United States, 2022-2023. Morb. Mortal. Wkly Rep. 72, 547–552 (2023).10.15585/mmwr.mm7220a2
172. Hermanussen L Tecovirimat for the treatment of severe Mpox in Germany Infection 2023 5 1 6
Hermanussen, L. et al. Tecovirimat for the treatment of severe Mpox in Germany. Infection 5, 1–6 (2023).
173. Shishkina LN Safety and pharmacokinetics of the substance of the anti-smallpox drug NIOCH-14 after oral administration to laboratory animals Viruses 2023 15 205 10.3390/v15010205 36680245
Shishkina, L. N. et al. Safety and pharmacokinetics of the substance of the anti-smallpox drug NIOCH-14 after oral administration to laboratory animals. Viruses 15, 205 (2023).36680245 10.3390/v15010205
174. Mazurkov OY New effective chemically synthesized anti-smallpox compound NIOCH-14 J. Gen. Virol. 2016 97 1229 1239 10.1099/jgv.0.000422 26861777
Mazurkov, O. Y. et al. New effective chemically synthesized anti-smallpox compound NIOCH-14. J. Gen. Virol. 97, 1229–1239 (2016).26861777 10.1099/jgv.0.000422
175. Kabanov AS A comparative study of the antiviral activity of chemical compounds concerning the orthopoxviruses experiments in vivo Vopr. Virusol. 2013 58 39 43 24354064
Kabanov, A. S. et al. A comparative study of the antiviral activity of chemical compounds concerning the orthopoxviruses experiments in vivo. Vopr. Virusol. 58, 39–43 (2013).24354064
176. Bloch EM The potential role of passive antibody-based therapies as treatments for Monkeypox mBio 2022 13 e0286222 10.1128/mbio.02862-22 36314809
Bloch, E. M. et al. The potential role of passive antibody-based therapies as treatments for Monkeypox. mBio 13, e0286222 (2022).36314809 10.1128/mbio.02862-22
177. Saghazadeh A Rezaei N Insights on Mpox virus infection immunopathogenesis Rev. Med. Virol. 2023 33 e2426 10.1002/rmv.2426 36738134
Saghazadeh, A. & Rezaei, N. Insights on Mpox virus infection immunopathogenesis. Rev. Med. Virol. 33, e2426 (2023).36738134 10.1002/rmv.2426
178. Li H The land-scape of immune response to monkeypox virus EBioMedicine 2023 87 104424 10.1016/j.ebiom.2022.104424 36584594
Li, H. et al. The land-scape of immune response to monkeypox virus. EBioMedicine 87, 104424 (2023).36584594 10.1016/j.ebiom.2022.104424
179. Shchelkunova GA Shchelkunov SN Immunomodulating drugs based on poxviral proteins BioDrugs 2016 30 9 16 10.1007/s40259-016-0158-5 26820996
Shchelkunova, G. A. & Shchelkunov, S. N. Immunomodulating drugs based on poxviral proteins. BioDrugs 30, 9–16 (2016).26820996 10.1007/s40259-016-0158-5
180. Mack TM Noble J Jr. Thomas DB A prospective study of serum antibody and protection against smallpox Am. J. Trop. Med. Hyg. 1972 21 214 218 10.4269/ajtmh.1972.21.214 5061278
Mack, T. M., Noble, J. Jr. & Thomas, D. B. A prospective study of serum antibody and protection against smallpox. Am. J. Trop. Med. Hyg. 21, 214–218 (1972).5061278 10.4269/ajtmh.1972.21.214
181. Gilchuk I Cross-neutralizing and protective human antibody specificities to poxvirus infections Cell 2016 167 684 694.e689 10.1016/j.cell.2016.09.049 27768891
Gilchuk, I. et al. Cross-neutralizing and protective human antibody specificities to poxvirus infections. Cell 167, 684–694.e689 (2016).27768891 10.1016/j.cell.2016.09.049
182. Galmiche MC Goenaga J Wittek R Rindisbacher L Neutralizing and protective antibodies directed against vaccinia virus envelope antigens Virology 1999 254 71 80 10.1006/viro.1998.9516 9927575
Galmiche, M. C., Goenaga, J., Wittek, R. & Rindisbacher, L. Neutralizing and protective antibodies directed against vaccinia virus envelope antigens. Virology 254, 71–80 (1999).9927575 10.1006/viro.1998.9516
183. Edghill-Smith Y Smallpox vaccine-induced antibodies are necessary and sufficient for protection against monkeypox virus Nat. Med. 2005 11 740 747 10.1038/nm1261 15951823
Edghill-Smith, Y. et al. Smallpox vaccine-induced antibodies are necessary and sufficient for protection against monkeypox virus. Nat. Med. 11, 740–747 (2005).15951823 10.1038/nm1261
184. Yi Mohammadi JJ Franks K Hines S Effectiveness of professional oral health care intervention on the oral health of residents with dementia in residential aged care facilities: a systematic review protocol JBI Database Syst. Rev. Implement. Rep. 2015 13 110 122 10.11124/jbisrir-2015-2330
Yi Mohammadi, J. J., Franks, K. & Hines, S. Effectiveness of professional oral health care intervention on the oral health of residents with dementia in residential aged care facilities: a systematic review protocol. JBI Database Syst. Rev. Implement. Rep. 13, 110–122 (2015).10.11124/jbisrir-2015-2330
185. Shearer JD Siemann L Gerkovich M House RV Biological activity of an intravenous preparation of human vaccinia immune globulin in mouse models of vaccinia virus infection Antimicrob. Agents Chemother. 2005 49 2634 2641 10.1128/AAC.49.7.2634-2641.2005 15980330
Shearer, J. D., Siemann, L., Gerkovich, M. & House, R. V. Biological activity of an intravenous preparation of human vaccinia immune globulin in mouse models of vaccinia virus infection. Antimicrob. Agents Chemother. 49, 2634–2641 (2005).15980330 10.1128/AAC.49.7.2634-2641.2005
186. Thet AK The use of vaccinia immune globulin in the treatment of severe Mpox. virus infection in human immunodeficiency virus/AIDS Clin. Infect. Dis. 2023 76 1671 1673 10.1093/cid/ciac971 36571287
Thet, A. K. et al. The use of vaccinia immune globulin in the treatment of severe Mpox. virus infection in human immunodeficiency virus/AIDS. Clin. Infect. Dis. 76, 1671–1673 (2023).36571287 10.1093/cid/ciac971
187. Denkinger CM Anti-SARS-CoV-2 antibody-containing plasma improves outcome in patients with hematologic or solid cancer and severe COVID-19: a randomized clinical trial Nat. Cancer 2023 4 96 107 36581734
Denkinger, C. M. et al. Anti-SARS-CoV-2 antibody-containing plasma improves outcome in patients with hematologic or solid cancer and severe COVID-19: a randomized clinical trial. Nat. Cancer 4, 96–107 (2023).36581734
188. Marconato M Antibodies from convalescent plasma promote SARS-CoV-2 clearance in individuals with and without endogenous antibody response J. Clin. Investig. 2022 132 e158190 10.1172/JCI158190 35482408
Marconato, M. et al. Antibodies from convalescent plasma promote SARS-CoV-2 clearance in individuals with and without endogenous antibody response. J. Clin. Investig. 132, e158190 (2022).35482408 10.1172/JCI158190
189. Engelmayer J Vaccinia virus inhibits the maturation of human dendritic cells: a novel mechanism of immune evasion J. Immunol. 1999 163 6762 6768 10.4049/jimmunol.163.12.6762 10586075
Engelmayer, J. et al. Vaccinia virus inhibits the maturation of human dendritic cells: a novel mechanism of immune evasion. J. Immunol. 163, 6762–6768 (1999).10586075 10.4049/jimmunol.163.12.6762
190. Li P Disruption of MHC class II-restricted antigen presentation by vaccinia virus J. Immunol. 2005 175 6481 6488 10.4049/jimmunol.175.10.6481 16272302
Li, P. et al. Disruption of MHC class II-restricted antigen presentation by vaccinia virus. J. Immunol. 175, 6481–6488 (2005).16272302 10.4049/jimmunol.175.10.6481
191. Humrich JY Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells Eur. J. Immunol. 2007 37 954 965 10.1002/eji.200636230 17357104
Humrich, J. Y. et al. Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells. Eur. J. Immunol. 37, 954–965 (2007).17357104 10.1002/eji.200636230
192. Chahroudi A Vaccinia virus tropism for primary hematolymphoid cells is determined by restricted expression of a unique virus receptor J. Virol. 2005 79 10397 10407 10.1128/JVI.79.16.10397-10407.2005 16051832
Chahroudi, A. et al. Vaccinia virus tropism for primary hematolymphoid cells is determined by restricted expression of a unique virus receptor. J. Virol. 79, 10397–10407 (2005).16051832 10.1128/JVI.79.16.10397-10407.2005
193. Reynoso GV Lymph node conduits transport virions for rapid T cell activation Nat. Immunol. 2019 20 602 612 10.1038/s41590-019-0342-0 30886418
Reynoso, G. V. et al. Lymph node conduits transport virions for rapid T cell activation. Nat. Immunol. 20, 602–612 (2019).30886418 10.1038/s41590-019-0342-0
194. Fischer MA CD11b+, Ly6G+ cells produce type I interferon and exhibit tissue-protective properties following peripheral virus infection PLoS Pathog. 2011 7 e1002374 10.1371/journal.ppat.1002374 22102816
Fischer, M. A. et al. CD11b+, Ly6G+ cells produce type I interferon and exhibit tissue-protective properties following peripheral virus infection. PLoS Pathog. 7, e1002374 (2011).22102816 10.1371/journal.ppat.1002374
195. Earl PL Americo JL Moss B Natural killer cells expanded in vivo or ex vivo with IL-15 overcomes the inherent susceptibility of CAST mice to lethal infection with orthopoxviruses PLoS Pathog. 2020 16 e1008505 10.1371/journal.ppat.1008505 32320436
Earl, P. L., Americo, J. L. & Moss, B. Natural killer cells expanded in vivo or ex vivo with IL-15 overcomes the inherent susceptibility of CAST mice to lethal infection with orthopoxviruses. PLoS Pathog. 16, e1008505 (2020).32320436 10.1371/journal.ppat.1008505
196. Song H Monkeypox virus infection of rhesus macaques induces massive expansion of natural killer cells but suppresses natural killer cell functions PLoS One 2013 8 e77804 10.1371/journal.pone.0077804 24147080
Song, H. et al. Monkeypox virus infection of rhesus macaques induces massive expansion of natural killer cells but suppresses natural killer cell functions. PLoS One 8, e77804 (2013).24147080 10.1371/journal.pone.0077804
197. Adamo S Memory profiles distinguish cross-reactive and virus-specific T cell immunity to mpox Cell Host Microbe 2023 31 928 936.e924 10.1016/j.chom.2023.04.015 37236191
Adamo, S. et al. Memory profiles distinguish cross-reactive and virus-specific T cell immunity to mpox. Cell Host Microbe 31, 928–936.e924 (2023).37236191 10.1016/j.chom.2023.04.015
198. Grifoni A Defining antigen targets to dissect vaccinia virus and monkeypox virus-specific T cell responses in humans Cell Host Microbe 2022 30 1662 1670.e1664 10.1016/j.chom.2022.11.003 36463861
Grifoni, A. et al. Defining antigen targets to dissect vaccinia virus and monkeypox virus-specific T cell responses in humans. Cell Host Microbe 30, 1662–1670.e1664 (2022).36463861 10.1016/j.chom.2022.11.003
199. Lum FM Monkeypox: disease epidemiology, host immunity and clinical interventions Nat. Rev. Immunol. 2022 22 597 613 10.1038/s41577-022-00775-4 36064780
Lum, F. M. et al. Monkeypox: disease epidemiology, host immunity and clinical interventions. Nat. Rev. Immunol. 22, 597–613 (2022).36064780 10.1038/s41577-022-00775-4
200. Méndez-Lagares G Memory T cell proliferation before hepatitis C virus therapy predicts antiviral immune responses and treatment success J. Immunol. 2018 200 1124 1132 10.4049/jimmunol.1701364 29263212
Méndez-Lagares, G. et al. Memory T cell proliferation before hepatitis C virus therapy predicts antiviral immune responses and treatment success. J. Immunol. 200, 1124–1132 (2018).29263212 10.4049/jimmunol.1701364
201. Zhang M Circulating T follicular helper cells are associated with rapid virological response in chronic hepatitis C patients undergoing peginterferon therapy Int. Immunopharmacol. 2016 34 235 243 10.1016/j.intimp.2016.03.005 26971227
Zhang, M. et al. Circulating T follicular helper cells are associated with rapid virological response in chronic hepatitis C patients undergoing peginterferon therapy. Int. Immunopharmacol. 34, 235–243 (2016).26971227 10.1016/j.intimp.2016.03.005
202. Nakatsuka K Ribavirin contributes to eradicate hepatitis C virus through polarization of T helper 1/2 cell balance into T helper 1 dominance World J. Hepatol. 2015 7 2590 2596 10.4254/wjh.v7.i25.2590 26557951
Nakatsuka, K. et al. Ribavirin contributes to eradicate hepatitis C virus through polarization of T helper 1/2 cell balance into T helper 1 dominance. World J. Hepatol. 7, 2590–2596 (2015).26557951 10.4254/wjh.v7.i25.2590
203. Grubczak K Effects of pegylated interferon alpha and ribavirin (pegIFN-α/RBV) therapeutic approach on regulatory T cells in HCV-monoinfected and HCV/HIV-coinfected patients Viruses 2021 13 1448 10.3390/v13081448 34452314
Grubczak, K. et al. Effects of pegylated interferon alpha and ribavirin (pegIFN-α/RBV) therapeutic approach on regulatory T cells in HCV-monoinfected and HCV/HIV-coinfected patients. Viruses 13, 1448 (2021).34452314 10.3390/v13081448
204. Essa S Al-Attiyah R Siddique I Al-Nakib W Modulation of immune cell subsets by hepatitis C virus and antiviral therapy in early virological response HCV genotype 4-infected patients with compensated liver disease Med. Princ. Pract. 2021 30 168 177 10.1159/000511783 32966988
Essa, S., Al-Attiyah, R., Siddique, I. & Al-Nakib, W. Modulation of immune cell subsets by hepatitis C virus and antiviral therapy in early virological response HCV genotype 4-infected patients with compensated liver disease. Med. Princ. Pract. 30, 168–177 (2021).32966988 10.1159/000511783
205. Riboldi P Gerosa M Meroni PL Pidotimod: a reappraisal Int. J. Immunopathol. Pharmacol. 2009 22 255 262 10.1177/039463200902200201 19505378
Riboldi, P., Gerosa, M. & Meroni, P. L. Pidotimod: a reappraisal. Int. J. Immunopathol. Pharmacol. 22, 255–262 (2009).19505378 10.1177/039463200902200201
206. Ding L Luo K Feng CG Oehlers SH Pidotimod increases inflammation in wounded zebrafish embryos Fish Shellfish Immunol. 2022 120 429 433 10.1016/j.fsi.2021.12.013 34922016
Ding, L., Luo, K., Feng, C. G. & Oehlers, S. H. Pidotimod increases inflammation in wounded zebrafish embryos. Fish Shellfish Immunol. 120, 429–433 (2022).34922016 10.1016/j.fsi.2021.12.013
207. Zhao N Pidotimod: a review of its pharmacological features and clinical effectiveness in respiratory tract infections Expert Rev. Anti-Infect. Ther. 2019 17 803 818 10.1080/14787210.2019.1679118 31603361
Zhao, N. et al. Pidotimod: a review of its pharmacological features and clinical effectiveness in respiratory tract infections. Expert Rev. Anti-Infect. Ther. 17, 803–818 (2019).31603361 10.1080/14787210.2019.1679118
208. Esposito S Immunomodulatory activity of pidotimod administered with standard antibiotic therapy in children hospitalized for community-acquired pneumonia J. Transl. Med. 2015 13 288 10.1186/s12967-015-0649-z 26335787
Esposito, S. et al. Immunomodulatory activity of pidotimod administered with standard antibiotic therapy in children hospitalized for community-acquired pneumonia. J. Transl. Med. 13, 288 (2015).26335787 10.1186/s12967-015-0649-z
209. Santus P Anti-inflammatory effects of immunostimulation in patients with COVID-19 pneumonia J. Clin. Med. 2021 10 5765 10.3390/jcm10245765 34945060
Santus, P. et al. Anti-inflammatory effects of immunostimulation in patients with COVID-19 pneumonia. J. Clin. Med. 10, 5765 (2021).34945060 10.3390/jcm10245765
210. Tao N Thymosin α1 and its role in viral infectious diseases: the mechanism and clinical application Molecules 2023 28 3539 10.3390/molecules28083539 37110771
Tao, N. et al. Thymosin α1 and its role in viral infectious diseases: the mechanism and clinical application. Molecules 28, 3539 (2023).37110771 10.3390/molecules28083539
211. Binder U Skerra A PASylated thymosin α1: a long-acting immunostimulatory peptide for applications in oncology and virology Int. J. Mol. Sci. 2020 22 124 10.3390/ijms22010124 33374407
Binder, U. & Skerra, A. PASylated thymosin α1: a long-acting immunostimulatory peptide for applications in oncology and virology. Int. J. Mol. Sci. 22, 124 (2020).33374407 10.3390/ijms22010124
212. Minutolo A Thymosin alpha 1 restores the immune homeostasis in lymphocytes during post-acute sequelae of SARS-CoV-2 infection Int. Immunopharmacol. 2023 118 110055 10.1016/j.intimp.2023.110055 36989892
Minutolo, A. et al. Thymosin alpha 1 restores the immune homeostasis in lymphocytes during post-acute sequelae of SARS-CoV-2 infection. Int. Immunopharmacol. 118, 110055 (2023).36989892 10.1016/j.intimp.2023.110055
213. Chen M Combination of gemcitabine and thymosin alpha 1 exhibit a better anti-tumor effect on nasal natural killer/T-cell lymphoma Int. Immunopharmacol. 2021 98 107829 10.1016/j.intimp.2021.107829 34119916
Chen, M. et al. Combination of gemcitabine and thymosin alpha 1 exhibit a better anti-tumor effect on nasal natural killer/T-cell lymphoma. Int. Immunopharmacol. 98, 107829 (2021).34119916 10.1016/j.intimp.2021.107829
214. Carta S Silvestri M Rossi GA Modulation of airway epithelial cell functions by Pidotimod: NF-kB cytoplasmatic expression and its nuclear translocation are associated with an increased TLR-2 expression Ital. J. Pediatr. 2013 39 29 10.1186/1824-7288-39-29 23663325
Carta, S., Silvestri, M. & Rossi, G. A. Modulation of airway epithelial cell functions by Pidotimod: NF-kB cytoplasmatic expression and its nuclear translocation are associated with an increased TLR-2 expression. Ital. J. Pediatr. 39, 29 (2013).23663325 10.1186/1824-7288-39-29
215. Kindrachuk J Systems kinomics demonstrates Congo Basin monkeypox virus infection selectively modulates host cell signaling responses as compared to West African monkeypox virus Mol. Cell Proteom. 2012 11 M111.015701 10.1074/mcp.M111.015701
Kindrachuk, J. et al. Systems kinomics demonstrates Congo Basin monkeypox virus infection selectively modulates host cell signaling responses as compared to West African monkeypox virus. Mol. Cell Proteom. 11, M111.015701 (2012).10.1074/mcp.M111.015701
216. Kataria R Kaur S Kaundal R Deciphering the complete human-monkeypox virus interactome: Identifying immune responses and potential drug targets Front. Immunol. 2023 14 1116988 10.3389/fimmu.2023.1116988 37051239
Kataria, R., Kaur, S. & Kaundal, R. Deciphering the complete human-monkeypox virus interactome: Identifying immune responses and potential drug targets. Front. Immunol. 14, 1116988 (2023).37051239 10.3389/fimmu.2023.1116988
217. Banham AH Smith GL Characterization of vaccinia virus gene B12R J. Gen. Virol. 1993 74 2807 2812 10.1099/0022-1317-74-12-2807 8277291
Banham, A. H. & Smith, G. L. Characterization of vaccinia virus gene B12R. J. Gen. Virol. 74, 2807–2812 (1993).8277291 10.1099/0022-1317-74-12-2807
218. Suraweera CD Hinds MG Kvansakul M Poxviral strategies to overcome host cell apoptosis Pathogens 2020 10 6 10.3390/pathogens10010006 33374867
Suraweera, C. D., Hinds, M. G. & Kvansakul, M. Poxviral strategies to overcome host cell apoptosis. Pathogens 10, 6 (2020).33374867 10.3390/pathogens10010006
219. Klaas L Diversity of cell death signaling pathways in macrophages upon infection with modified vaccinia virus Ankara (MVA) Cell Death Dis. 2021 12 1011 10.1038/s41419-021-04286-3 34711816
Klaas, L. et al. Diversity of cell death signaling pathways in macrophages upon infection with modified vaccinia virus Ankara (MVA). Cell Death Dis. 12, 1011 (2021).34711816 10.1038/s41419-021-04286-3
220. Myskiw C Nigericin is a potent inhibitor of the early stage of vaccinia virus replication Antiviral Res. 2010 88 304 310 10.1016/j.antiviral.2010.10.001 20951746
Myskiw, C. et al. Nigericin is a potent inhibitor of the early stage of vaccinia virus replication. Antiviral Res. 88, 304–310 (2010).20951746 10.1016/j.antiviral.2010.10.001
221. Nichols RJ Wiebe MS Traktman P The vaccinia-related kinases phosphorylate the N’ terminus of BAF, regulating its interaction with DNA and its retention in the nucleus Mol. Biol. Cell 2006 17 2451 2464 10.1091/mbc.e05-12-1179 16495336
Nichols, R. J., Wiebe, M. S. & Traktman, P. The vaccinia-related kinases phosphorylate the N’ terminus of BAF, regulating its interaction with DNA and its retention in the nucleus. Mol. Biol. Cell 17, 2451–2464 (2006).16495336 10.1091/mbc.e05-12-1179
222. Boyle KA Traktman P Members of a novel family of mammalian protein kinases complement the DNA-negative phenotype of a vaccinia virus ts mutant defective in the B1 kinase J. Virol. 2004 78 1992 2005 10.1128/JVI.78.4.1992-2005.2004 14747564
Boyle, K. A. & Traktman, P. Members of a novel family of mammalian protein kinases complement the DNA-negative phenotype of a vaccinia virus ts mutant defective in the B1 kinase. J. Virol. 78, 1992–2005 (2004).14747564 10.1128/JVI.78.4.1992-2005.2004
223. Rodrigues Garcia D Design of inhibitors of thymidylate kinase from Variola virus as new selective drugs against smallpox: part II J. Biomol. Struct. Dyn. 2019 37 4569 4579 10.1080/07391102.2018.1554510 30488769
Rodrigues Garcia, D. et al. Design of inhibitors of thymidylate kinase from Variola virus as new selective drugs against smallpox: part II. J. Biomol. Struct. Dyn. 37, 4569–4579 (2019).30488769 10.1080/07391102.2018.1554510
224. Ajmal A Computer-assisted drug repurposing for thymidylate kinase drug target in monkeypox virus Front. Cell Infect. Microbiol. 2023 13 1159389 10.3389/fcimb.2023.1159389 37313340
Ajmal, A. et al. Computer-assisted drug repurposing for thymidylate kinase drug target in monkeypox virus. Front. Cell Infect. Microbiol. 13, 1159389 (2023).37313340 10.3389/fcimb.2023.1159389
225. Khan A Structure-based design of promising natural products to inhibit thymidylate kinase from Monkeypox virus and validation using free energy calculations Comput. Biol. Med. 2023 158 106797 10.1016/j.compbiomed.2023.106797 36966556
Khan, A. et al. Structure-based design of promising natural products to inhibit thymidylate kinase from Monkeypox virus and validation using free energy calculations. Comput. Biol. Med. 158, 106797 (2023).36966556 10.1016/j.compbiomed.2023.106797
226. Pourhajibagher M Bahador A Virtual screening and computational simulation analysis of antimicrobial photodynamic therapy using propolis-benzofuran A to control of Monkeypox Photodiagnosis Photodyn. Ther. 2023 41 103208 10.1016/j.pdpdt.2022.103208 36417972
Pourhajibagher, M. & Bahador, A. Virtual screening and computational simulation analysis of antimicrobial photodynamic therapy using propolis-benzofuran A to control of Monkeypox. Photodiagnosis Photodyn. Ther. 41, 103208 (2023).36417972 10.1016/j.pdpdt.2022.103208
227. Dao TL Corrigendum to “Infectious disease symptoms and microbial carriage among French medical students travelling abroad: a prospective study. Travel Med. Infect. Dis. 2023 34 102609 10.1016/j.tmaid.2023.102609
Dao, T. L. et al. Corrigendum to “Infectious disease symptoms and microbial carriage among French medical students travelling abroad: a prospective study.Travel Med. Infect. Dis. 34, 102609 (2023).10.1016/j.tmaid.2023.102609
228. Yang C Travel before, during and after the COVID-19 pandemic: exploring factors in essential travel using empirical data J Transp. Geogr. 2023 110 103640 10.1016/j.jtrangeo.2023.103640 37377632
Yang, C. et al. Travel before, during and after the COVID-19 pandemic: exploring factors in essential travel using empirical data. J Transp. Geogr. 110, 103640 (2023).37377632 10.1016/j.jtrangeo.2023.103640
229. Kmiec D Kirchhoff F Monkeypox: a new threat? Int. J. Mol. Sci. 2022 23 7886 10.3390/ijms23147866 35887234
Kmiec, D. & Kirchhoff, F. Monkeypox: a new threat? Int. J. Mol. Sci. 23, 7886 (2022).35887234 10.3390/ijms23147866
230. Harris E Global Monkeypox outbreaks spur drug research for the neglected disease JAMA. 2022 328 231 233 10.1001/jama.2022.11224 35767293
Harris, E. Global Monkeypox outbreaks spur drug research for the neglected disease. JAMA. 328, 231–233 (2022).35767293 10.1001/jama.2022.11224
231. Karim M Lo CW Einav S Preparing for the next viral threat with broad-spectrum antivirals J. Clin. Investig. 2023 133 e170236 10.1172/JCI170236 37259914
Karim, M., Lo, C. W. & Einav, S. Preparing for the next viral threat with broad-spectrum antivirals. J. Clin. Investig. 133, e170236 (2023).37259914 10.1172/JCI170236
232. Ezat AA The discovery of novel antivirals for the treatment of Mpox: is drug repurposing the answer? Expert Opin. Drug Discov. 2023 18 551 561 10.1080/17460441.2023.2199980 37032577
Ezat, A. A. et al. The discovery of novel antivirals for the treatment of Mpox: is drug repurposing the answer? Expert Opin. Drug Discov. 18, 551–561 (2023).37032577 10.1080/17460441.2023.2199980
233. Mercorelli B Palù G Loregian A Drug repurposing for viral infectious diseases: how far are we? Trends Microbiol. 2018 26 865 876 10.1016/j.tim.2018.04.004 29759926
Mercorelli, B., Palù, G. & Loregian, A. Drug repurposing for viral infectious diseases: how far are we? Trends Microbiol. 26, 865–876 (2018).29759926 10.1016/j.tim.2018.04.004
234. Ayon NJ High-throughput screening of natural product and synthetic molecule libraries for antibacterial drug discovery Metabolites 2023 13 625 10.3390/metabo13050625 37233666
Ayon, N. J. High-throughput screening of natural product and synthetic molecule libraries for antibacterial drug discovery. Metabolites 13, 625 (2023).37233666 10.3390/metabo13050625
235. Dueñas ME Advances in high-throughput mass spectrometry in drug discovery EMBO Mol. Med. 2023 15 e14850 10.15252/emmm.202114850 36515561
Dueñas, M. E. et al. Advances in high-throughput mass spectrometry in drug discovery. EMBO Mol. Med. 15, e14850 (2023).36515561 10.15252/emmm.202114850
236. Bon M Bilsland A Bower J McAulay K Fragment-based drug discovery-the importance of high-quality molecule libraries Mol. Oncol. 2022 16 3761 3777 10.1002/1878-0261.13277 35749608
Bon, M., Bilsland, A., Bower, J. & McAulay, K. Fragment-based drug discovery-the importance of high-quality molecule libraries. Mol. Oncol. 16, 3761–3777 (2022).35749608 10.1002/1878-0261.13277
237. Bassani D Moro S Past, present, and future perspectives on computer-aided drug design methodologies Molecules 2023 28 3906 10.3390/molecules28093906 37175316
Bassani, D. & Moro, S. Past, present, and future perspectives on computer-aided drug design methodologies. Molecules 28, 3906 (2023).37175316 10.3390/molecules28093906
238. Sadybekov AV Katritch V Computational approaches streamlining drug discovery Nature 2023 616 673 685 10.1038/s41586-023-05905-z 37100941
Sadybekov, A. V. & Katritch, V. Computational approaches streamlining drug discovery. Nature 616, 673–685 (2023).37100941 10.1038/s41586-023-05905-z
239. Vemula D CADD, AI and ML in drug discovery: a comprehensive review Eur. J. Pharm. Sci. 2023 181 106324 10.1016/j.ejps.2022.106324 36347444
Vemula, D. et al. CADD, AI and ML in drug discovery: a comprehensive review. Eur. J. Pharm. Sci. 181, 106324 (2023).36347444 10.1016/j.ejps.2022.106324
240. Luna N Monkeypox virus (MPXV) genomics: a mutational and phylogenomic analyses of B.1 lineages Travel Med. Infect. Dis. 2023 52 102551 10.1016/j.tmaid.2023.102551 36746267
Luna, N. et al. Monkeypox virus (MPXV) genomics: a mutational and phylogenomic analyses of B.1 lineages. Travel Med. Infect. Dis. 52, 102551 (2023).36746267 10.1016/j.tmaid.2023.102551
241. Salamango DJ Harris RS Demystifying cell cycle arrest by HIV-1 Vif Trends Microbiol. 2021 29 381 384 10.1016/j.tim.2021.01.001 33478820
Salamango, D. J. & Harris, R. S. Demystifying cell cycle arrest by HIV-1 Vif. Trends Microbiol. 29, 381–384 (2021).33478820 10.1016/j.tim.2021.01.001
242. Azimi FC Lee JE Structural perspectives on HIV-1 Vif and APOBEC3 restriction factor interactions Protein Sci. 2020 29 391 406 10.1002/pro.3729 31518043
Azimi, F. C. & Lee, J. E. Structural perspectives on HIV-1 Vif and APOBEC3 restriction factor interactions. Protein Sci. 29, 391–406 (2020).31518043 10.1002/pro.3729
243. Colson P Sequencing of monkeypox virus from infected patients reveals viral genomes with APOBEC3-like editing, gene inactivation, and bacterial agents of skin superinfection J. Med. Virol. 2023 95 e28799 10.1002/jmv.28799 37342884
Colson, P. et al. Sequencing of monkeypox virus from infected patients reveals viral genomes with APOBEC3-like editing, gene inactivation, and bacterial agents of skin superinfection. J. Med. Virol. 95, e28799 (2023).37342884 10.1002/jmv.28799
244. Dobrovolná M Brázda V Warner EF Bidula S Inverted repeats in the monkeypox virus genome are hot spots for mutation J. Med. Virol. 2023 95 e28322 10.1002/jmv.28322 36400742
Dobrovolná, M., Brázda, V., Warner, E. F. & Bidula, S. Inverted repeats in the monkeypox virus genome are hot spots for mutation. J. Med. Virol. 95, e28322 (2023).36400742 10.1002/jmv.28322
245. Dumonteil E Herrera C Sabino-Santos G Monkeypox virus evolution before 2022 outbreak Emerg. Infect. Dis. 2023 29 451 453 10.3201/eid2902.220962 36692511
Dumonteil, E., Herrera, C. & Sabino-Santos, G. Monkeypox virus evolution before 2022 outbreak. Emerg. Infect. Dis. 29, 451–453 (2023).36692511 10.3201/eid2902.220962
246. Blanco-González A The role of AI in drug discovery: challenges, opportunities, and strategies Pharmaceuticals 2023 16 891 10.3390/ph16060891 37375838
Blanco-González, A. et al. The role of AI in drug discovery: challenges, opportunities, and strategies. Pharmaceuticals 16, 891 (2023).37375838 10.3390/ph16060891
247. Chadaga K Application of artificial intelligence techniques for Monkeypox: a systematic review Diagnostics 2023 13 824 10.3390/diagnostics13050824 36899968
Chadaga, K. et al. Application of artificial intelligence techniques for Monkeypox: a systematic review. Diagnostics 13, 824 (2023).36899968 10.3390/diagnostics13050824
248. Cheng K Talk with ChatGPT about the outbreak of Mpox in 2022: reflections and suggestions from AI dimensions Ann. Biomed. Eng. 2023 51 870 874 10.1007/s10439-023-03196-z 37031289
Cheng, K. et al. Talk with ChatGPT about the outbreak of Mpox in 2022: reflections and suggestions from AI dimensions. Ann. Biomed. Eng. 51, 870–874 (2023).37031289 10.1007/s10439-023-03196-z
249. Gentile F Oprea TI Tropsha A Cherkasov A Surely you are joking, Mr Docking! Chem. Soc. Rev. 2023 52 872 878 10.1039/D2CS00948J 36644974
Gentile, F., Oprea, T. I., Tropsha, A. & Cherkasov, A. Surely you are joking, Mr Docking! Chem. Soc. Rev. 52, 872–878 (2023).36644974 10.1039/D2CS00948J
250. Doan S Severe corneal involvement associated with Mpox infection JAMA Ophthalmol. 2023 141 402 403 10.1001/jamaophthalmol.2023.0022 36892826
Doan, S. et al. Severe corneal involvement associated with Mpox infection. JAMA Ophthalmol. 141, 402–403 (2023).36892826 10.1001/jamaophthalmol.2023.0022
251. Ogoina D Mohammed A Yinka-Ogunleye A Ihekweazu C A case of suicide during the 2017 monkeypox outbreak in Nigeria IJID Reg. 2022 3 226 227 10.1016/j.ijregi.2022.04.004 35755463
Ogoina, D., Mohammed, A., Yinka-Ogunleye, A. & Ihekweazu, C. A case of suicide during the 2017 monkeypox outbreak in Nigeria. IJID Reg. 3, 226–227 (2022).35755463 10.1016/j.ijregi.2022.04.004
252. Hanna E Abadi R Abbas O Imiquimod in dermatology: an overview Int. J. Dermatol. 2016 55 831 844 10.1111/ijd.13235 27387373
Hanna, E., Abadi, R. & Abbas, O. Imiquimod in dermatology: an overview. Int. J. Dermatol. 55, 831–844 (2016).27387373 10.1111/ijd.13235
253. Gupta AK Browne M Bluhm R Imiquimod: a review J. Cutan Med. Surg. 2002 6 554 560 10.1177/120347540200600607 12362256
Gupta, A. K., Browne, M. & Bluhm, R. Imiquimod: a review. J. Cutan Med. Surg. 6, 554–560 (2002).12362256 10.1177/120347540200600607
254. Skinner RB Jr. Imiquimod as an immune response modulator in infectious conditions Postgrad. Med. 2002 112 8 16 19667608
Skinner, R. B. Jr. Imiquimod as an immune response modulator in infectious conditions. Postgrad. Med. 112, 8–16 (2002).19667608
255. Hengge UR Cusini M Topical immunomodulators for the treatment of external genital warts, cutaneous warts and molluscum contagiosum Br. J. Dermatol. 2003 149 15 19 10.1046/j.0366-077X.2003.05623.x 14616340
Hengge, U. R. & Cusini, M. Topical immunomodulators for the treatment of external genital warts, cutaneous warts and molluscum contagiosum. Br. J. Dermatol. 149, 15–19 (2003).14616340 10.1046/j.0366-077X.2003.05623.x
256. Dahl MV Imiquimod: a cytokine inducer J. Am. Acad. Dermatol. 2002 47 S205 S208 10.1067/mjd.2002.126586 12271278
Dahl, M. V. Imiquimod: a cytokine inducer. J. Am. Acad. Dermatol. 47, S205–S208 (2002).12271278 10.1067/mjd.2002.126586
257. Roper RL Monkeypox (Mpox) requires continued surveillance, vaccines, therapeutics and mitigating strategies Vaccine 2023 41 3171 3177 10.1016/j.vaccine.2023.04.010 37088603
Roper, R. L. et al. Monkeypox (Mpox) requires continued surveillance, vaccines, therapeutics and mitigating strategies. Vaccine 41, 3171–3177 (2023).37088603 10.1016/j.vaccine.2023.04.010
258. Schildhauer S Reduced odds of Mpox-associated hospitalization among persons who received JYNNEOS Vaccine - California, May 2022-May 2023 Morb. Mortal. Wkly Rep. 2023 72 992 996 10.15585/mmwr.mm7236a4
Schildhauer, S. et al. Reduced odds of Mpox-associated hospitalization among persons who received JYNNEOS Vaccine - California, May 2022-May 2023. Morb. Mortal. Wkly Rep. 72, 992–996 (2023).10.15585/mmwr.mm7236a4
259. Sammartino JC Characterization of immune response against monkeypox virus in cohorts of infected patients, historic and newly vaccinated subjects J. Med. Virol. 2023 95 e28778 10.1002/jmv.28778 37212258
Sammartino, J. C. et al. Characterization of immune response against monkeypox virus in cohorts of infected patients, historic and newly vaccinated subjects. J. Med. Virol. 95, e28778 (2023).37212258 10.1002/jmv.28778
260. Saadh MJ Progress and prospects on vaccine development against monkeypox infection Microb. Pathog. 2023 180 106156 10.1016/j.micpath.2023.106156 37201635
Saadh, M. J. et al. Progress and prospects on vaccine development against monkeypox infection. Microb. Pathog. 180, 106156 (2023).37201635 10.1016/j.micpath.2023.106156
261. Abdelaal A Preventing the next pandemic: is live vaccine efficacious against Monkeypox, or is there a need for killed virus and mRNA vaccines? Vaccines 2022 10 1419 10.3390/vaccines10091419 36146497
Abdelaal, A. et al. Preventing the next pandemic: is live vaccine efficacious against Monkeypox, or is there a need for killed virus and mRNA vaccines? Vaccines 10, 1419 (2022).36146497 10.3390/vaccines10091419
262. FDA. Monkeypox update: FDA authorizes emergency use of JYNNEOS vaccine to increase vaccine supply, https://www.fda.gov/news-events/press-announcements/monkeypox-update-fda-authorizes-emergency-use-jynneos-vaccine-increase-vaccine-supply (2022).
263. Eustaquio PC Salmon-Trejo LAT McGuire LC Ellington SR Epidemiologic and clinical features of mpox in adults aged >50 years—United States, May 2022–May 2023 Morb. Mortal. Wkly Rep. 2023 72 893 896 10.15585/mmwr.mm7233a3
Eustaquio, P. C., Salmon-Trejo, L. A. T., McGuire, L. C. & Ellington, S. R. Epidemiologic and clinical features of mpox in adults aged >50 years—United States, May 2022–May 2023. Morb. Mortal. Wkly Rep. 72, 893–896 (2023).10.15585/mmwr.mm7233a3
264. Cohn H Mpox vaccine and infection-driven human immune signatures: an immunological analysis of an observational study Lancet Infect. Dis. 2023 23 00352 00353 10.1016/S1473-3099(23)00352-3
Cohn, H. et al. Mpox vaccine and infection-driven human immune signatures: an immunological analysis of an observational study. Lancet Infect. Dis. 23, 00352–00353 (2023).10.1016/S1473-3099(23)00352-3
