==== Front Biomed Res Int Biomed Res Int BMRI BioMed Research International 2314-6133 2314-6141 Hindawi 10.1155/2020/3972390 Review Article Natural Products: Review for Their Effects of Anti-HBV https://orcid.org/0000-0002-9345-5631Liu Xuqiang 1 2 https://orcid.org/0000-0003-1583-9741Ma Changyang 1 https://orcid.org/0000-0002-0053-1923Liu Zhenhua liuzhenhua623@163.com 1 https://orcid.org/0000-0002-1822-6249Kang Wenyi kangweny@hotmail.com 1 2 3 1National R & D Center for Edible Fungus Processing Technology, Henan University, Kaifeng 475004, China 2Functional Food Engineering Technology Research Center, Henan Province, Kaifeng 475004, China 3Joint International Research Laboratory of Food & Medicine Resource Function, Henan University, Kaifeng, 475004 Henan Province, China Academic Editor: Abdul Ahad 2020 9 12 2020 2020 397239010 7 2020 13 11 2020 23 11 2020 Copyright © 2020 Xuqiang Liu et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Hepatitis B is a global infectious disease, seriously endangering human health. Currently, there are mainly interferons and nucleoside analogues treatment of hepatitis B in the clinic, which have certain therapeutic effects on hepatitis B, but their side effects and drug resistance are increasingly prominent. Therefore, it is urgently needed to discover and develop new anti-HBV drugs, especially natural products, which have novel, high efficiency, and low toxicity anti-HBV compounds with novel antiviral mechanisms. In this manuscript, the natural products (polysaccharides and 165 compounds) with the activity of antihepatitis B virus are discussed according to their chemical classes, including 14 phenylpropanoids, 8 flavonoids,12 xanthones, 13 anthroquinones, 47 terpenoids, 6 alkaloids, 15 enediynes, 11 aromatics, 18 phenylalanine dipeptides compounds, and 13 others. In addition, the anti-HBV mechanism and targets of natural product were also discussed. The aim of this review is to report new discoveries about anti-HBV natural products and to provide reference for researchers. Key Project in Science and Technology of Henan Province182102410083 ==== Body 1. Introduction Viral hepatitis B, referred to as hepatitis B, is a disease caused by the infection of hepatitis B virus (HBV, Figure 1). The infection of HBV can cause liver failure, acute or chronic hepatitis, cirrhosis, and even hepatocellular carcinoma (HCC). About 2 billion people worldwide are infected with HBV, of which 400 million are long-term carriers [1, 2]. According to research reports by the World Health Organization (WHO), about 600,000 people die of HBV infection or liver diseases related to HBV infection every year [3, 4]. China has the largest population of HBV-infected people worldwide and is confronting this large disease burden with efficient antiviral drugs. At present, there are mainly two kinds of drugs used in the clinic, namely, interferons (INFs) with antiviral and immunoregulatory functions and nucleoside analogues that can inhibit the reverse transcription of HBV [5, 6]. In recent years, although these drugs have a certain therapeutic effect on HBV infection in the clinic, there are serious side effects and drug resistance [7, 8]. Thus, there are more and more researchers focus on natural product [9–11]. Some researches report a variety of natural medicines with novel structure and anti-HBV activity, including some candidate drugs with good anti-HBV effects. However, these reports were mainly involved in isolation and identification of compounds with anti-HBV activity; the mechanisms and targets of compounds were less. The mechanism of clinical medicines (nucleoside analogues and interferon) on anti-HBV is basically clear, but the emergence of drug-resistant HBV mutants weakens the clinical effects. Thus, the development of safe and effective anti-HBV drugs with novel mechanism is the top priority in the current research [7, 12]. In this manuscript, in order to help researchers understand HBV and develop the anti-HBV drugs, all kinds of natural products (Table 1) with anti-HBV effects and the infection process of HBV (Figure 1) [13–17] were summarized. The types of natural products with anti-HBV activity include phenylpropanoids, flavonoids, alkaloids, terpenes, glycosides, and others (such as lactones and organic acids). 2. The Natural Products of Anti-HBV 2.1. Phenylpropanoids Phenylpropanins have a wide range of biological activities, including antitumor, antivirus, liver protection, and antioxidation. For example, a variety of lignans in fruits of Schisandra chinensis have liver protective effects and can reduce serum alanine aminotransferase level. Schisandrae esteril A and its analogues have been used in the treatment of chronic hepatitis in China [18]. 6-Hydroxyl-7-methoxyl-coumarin (1), isolated from the Streblus asper Lour core material, had significant anti-HBV effect on HepG 2.2.15 cells [19]. And the mechanism of compound 1 on anti-HBV effect may be related to its inhibition on secretion of hepatitis B virus surface antigen (HBsAg) and hepatitis B virus e antigen (HBeAg), and the IC50 were 29.60 μM (selective index, SI = 6.76) and 46.41 μM (SI = 4.31), respectively. Esculetin (2) from Microsorium fortunei (Moore) Ching. could not only inhibit the expression of the HBV antigens and HBV-DNA but also inhibit the expression of hepatitis B virus X(HBx) protein in a dose-dependent manner [20]. Chen et al. [21] isolated a series of phenylpropanins from the core material, bark and root of S. asper, all of which had significant anti-HBV activity. Among them, Magnatriol B (3) showed moderate anti-HBV activity by inhibiting the secretion of HBsAg and HBeAg with low cytotoxicity. Honokiol (4) showed significant anti-HBV activity and strong inhibition on HBsAg and HBeAg with IC50 of 3.14 μM (SI = 21.47) and 4.74 μM (SI = 14.22), respectively. The inhibition effect of honokiol on HBsAg and HBeAg was stronger than that of positive control, lamivudine. Isomagnolol (5) and isocarpine (6) from the bark and roots of S. asper showed significant anti-HBV activity by HepG 2.2.15 cell assay and significantly inhibited HBsAg secretion with IC50 of 10.34 μM and 3.67 μM, respectively. For inhibiting the secretion of HBeAg, IC50 was 8.83 μM and 14.67 μM, respectively, without cytotoxicity. Honokiol (7) and (7′R, 8′S, 7′R, 8′S)-erythron-Strebluslignanol G (8), isolated from methanol extract of roots of S. asper, have strong anti-HBV activity by inhibiting the secretion of HBsAg and HBeAg. In addition, compounds 7and 8 could significantly inhibit the replication of HBV-DNA, with IC50 of 9.02 and 8.67 μM, respectively [22, 23]. Coumarin lignan (9) isolated from the stem of Kadsura heteroclita could inhibit the production of HBsAg and HBeAg with concentration of 25 μg/mL. The inhibition of compound 9 (57% and 48%) was even better than that of positive control, lamivudine (10% and 46%) [24]. Niranthin (10), isolated from Phyllanthus niruri, could inhibit the secretion of HBsAg and HBeAg in dose-dependent, with IC50 values of 16.5 μM and 25.1 μM. The inhibition rates of 10 on HBsAg and HBeAg were 90.4% and 83.1% with 55.5 μM while the inhibition rates of lamivudine were 55.6% and 44.5% with 43.6 μM. The anti-HBV effect of compound 10 was better than that of lamivudine. The inhibition rates of compound 10 on DHBV-DNA, HBsAg, and HBeAg were higher than that of lamivudine, and the recovery rate was smaller after drug withdrawal, indicating that compound 10 had a good prospect in the development of new anti-HBV drugs in vivo [25]. (+)-Dehydrod-iconiferyl alcohol (11) and dehydrozingerone (12) showed moderate inhibitory activities on the secretion of HBsAg with IC50 value of 1.94 mM (SI 1.06) and 0.50 mM (SI 2.88) [26]. (+)-Cycloolivil-4′-O-β-D-glucopyranoside (13) and syringaresinol 4″-O-β-D-glucopyranoside (14) showed inhibitory activity on HBsAg secretion with IC50 values of 0.31 ± 0.045 and 1.49 ± 0.033 mM. In particular, compound 13 exhibited inhibition not only on the secretions of HBsAg and HBeAg with IC50 values of 0.31 ± 0.045 mM (SI = 4.29) and 0.77 ± 0.076 mM (SI = 1.75), respectively, but also on HBV DNA replication with an IC50 value of 0.29 ± 0.034 mM (SI = 4.66) [27]. The chemical structures of compounds 1~14 showed in Figure 2. 2.2. Flavonoids Flavonoids have a wide range of biological activities, including anti-inflammatory, anticancer, and antibacterial. It has a prominent role in protecting liver; for example, silymarin shows significant effect on protecting liver and has successfully developed into a protect liver medicine [28]. Recently, flavonoids have been reported with good anti-HBV effect. Luteolin (15), isolated from Swertia macrosperma C. B. Clark, could significantly inhibit the secretion of HBsAg and HBeAg with IC50 values of 0.02 mM on HepG 2.2.15 cells in vitro [29]. Isovitexin (16) isolated from S. yunnanensis had good anti-HBV effect, which could not only inhibit the secretion of HBsAg and HBeAg, with IC50 values of 0.04 mM, <0.03 mM, and 0.23 mM, but also significantly inhibit the replication of HBV-DNA, with the IC50 values of 0.09 mM, <0.01 mM, and 0.05 mM [30]. Huang et al. [31] isolated LPRP-Et-97543 (17) from Liriopemuscari (Decne.) L.H.Bailey, which had significant anti-HBV activity and could significantly reduce the activity of Core, S, and preS promoters. Moreover, the mechanism may be that it inhibited the replication of viral DNA by regulating viral proteins. In recent years, molecular docking technology was used to screen the active ingredients against HBV, a 3D structure of HBV polymerase (Pol/RT) was modeled and docked with the active compounds, and quercetin (18) was proved that could enhance its anti-HBV activity up to 10% [32]. In addition, some researchers found that glabaarachalcone (19) and isopongachromene (20), isolated from P. pinnata, could bound with HBV-DNA polymerase protein target [33]. Isooriention (21), isolated from S. mussotii, displayed significant anti-HBV activities against the secretions of HBsAg and HBeAg with IC50 value of 0.79 and 1.12 mM, as well as HBV-DNA replication with IC50 value of 0.02 mM [34]. Epimedium Hyde II (22), a potential Chinese herbal active ingredient against HBV, could inhibit the replication of HBV-DNA and the expression of HBsAg and HBeAg in the serum of HBV-replicated C57BL/6 mice [35]. The chemical structures of compounds 15~22 showed in Figure 3. 2.3. Xanthones Norbellidifolin (23), 1,5,8-trihydroxy-3-methoxyxanthone (24), 2-C-β-D-glucopyranosyl-1,3,7-trihydroxyxanthone (25), norswertianolin (26), norswertianin-1-O-β-D-glucoside (27), 1,7-dihydroxy-3,8-dimethoxyxanthone (28), 7-O-[β-D-xylopyranosyl-(1 → 2)-β-D-xylopyranosyl]-1,8-dihydroxy-3-methoxyxanthone (29), and mangiferin (30) showed remarkable inhibition on HBV-DNA replication with IC50 values from 0.01 mM to 0.13 mM. Compounds 23-25 with three or more hydroxy groups showed significant inhibitory activity with IC50 values of 0.77, >0.98, and 0.21 mM for HBsAg, and <0.62, 0.35, and 0.04 mM for HBeAg, respectively. It was deduced that hydroxy groups in the xanthone structure were essential for maintaining the inhibitory effects on the secretion of HBsAg and HBeAg. Glycosidation of hydroxy groups led to activity decreasing against HBsAg and HBeAg by comparing the activity of compounds 24, 26, and 27. It was concluded that two or more hydroxy groups were essential for inhibiting HBV-DNA replication, and methylation of hydroxy groups decreased or abolished anti-HBV activity. In addition, the position of the hydroxy groups of the isolated xanthones did not significantly affect the inhibition on HBV-DNA replication. The preliminary structure-activity relationships were deduced as (1) the anti-HBV activity of xanthones depends on the structure and substitution pattern of the hydroxy groups; (2) the hydroxy groups play very important roles in the anti-HBV activity; (3) the anti-HBV activity will be decreased after methylation orglycosidation [36]. Methyl6,8-dihydroxy-3-methyl-9-oxo-9H-xanthene-1-carboxylate (31), isolated from mangrove-derived aciduric fungus Penicillium sp., inhibited HBsAg secretion more effectively than that of the positive control, 3TC, in a dose-dependent manner [37]. 1,8-Dihydroxy-3,5-dimethoxyxanthone (32), norswertianolin (33), and neolancerin (34), isolated from S. yunnanensis, had good anti-HBV effect. Among of them, compound 34 could not only inhibit the secretion of HBsAg and HBeAg, with IC50 values of 0.21, 0.10, and 1.51, but also significantly inhibit the replication of HBV-DNA, with the IC50 values of 0.09 mM, <0.01 mM, and 0.05 mM. However, compounds 32 and 33 only showed inhibitory effect on HBV-DNA replication, which may be caused by methylation or glycoylation of the hydroxyl group of the compounds [30]. 1,5,8-Trihydroxy-3-methoxyxanthone (35) exhibited significant inhibitory activity on HBV-DNA replication with IC50 values of 0. 09 and 0. 05 m mol·L−1 (SI of 10. 89) and showed potent activity against the secretion of HBeAg with IC50 values of 0. 35 (SI of ≥2. 80) [38]. The chemical structures of compounds 23~35 are shown in Figure 4. 2.4. Anthroquinones Anthroquinones, often found in the metabolites of lichens and fungi of higher plants and lower plants, have the functions of hemostasis, antisepsis, purgation, and diuretic. In recent years, the anti-HBV activity of anthroquinones was reported [39]. (−)-2′R-1-hydroxyisorhodoptilometrin (36), asterric acid (37), questinol (38), endo crocin (39), (+)-2′S-isorhodoptilometrin (40), sulochrin (41), monochlorsulochrin (42), and dihydrogeodin (43) were isolated from mangrove-derived aciduric fungus Penicillium sp. and inhibited HBsAg secretion more effectively than that of the positive control, 3TC, in a dose-dependent manner. Compared with 13% inhibition by 3TC, compounds 36 and 42 at 20 μM inhibited HBeAg secretion by 17 and 35%, respectively. Compound 36 showed much stronger antihepatitis B virus activity than that of the positive control, lamivudine, strongly inhibiting the secretion on HBsAg and HBeAg of HepG 2.2.15 cells. These results showed that extremophiles are a valuable resource of bioactive compounds, and that pH regulation is an effective strategy to induce metabolite production in aciduric fungi [37]. Peng et al. [40] found that 1,3-dihydroxy-2-hydroxymethyl-9,10-anthraquinone (44), Rubiadin (45), and Anthraquinone bile acid conjugates (46) have significant anti-HBV effects on HepG2.2.15 cells. The IC50 values of them were 12.41, 8.03, 17.05, and 8.13 g/mL, respectively. When the drug concentrations were 8 g/mL, the inhibitory rates of HBeAg were 61.42%, 43.79%, and 69.30%, respectively. The inhibitory rates of HBsAg secreted by cells were 6.15%, 23.34%, and 43.38%, respectively. Particularly, compound 45 could not only significantly decrease HBeAg and HBsAg secretion level and inhibit HBV-DNA replication but also inhibit the proliferation of the cells and HBx protein expression in a dose-dependent manner, which might become a novel anti-HBV drug candidate. Mohammad K et al. [41] reported that anti-HBV potential of AV-derived anthroquinones, possibly via HBV-DNA polymerase inhibition for the first time. Although aloin B (47) exhibited novel antiviral effect, aloe-emodin (48) appeared as the most promising anti-HBV natural drug with CYP3A4 activating property towards its enhanced therapeutic efficacy. Lan et al. [42] found that hypericin (49) could significantly reduce the expression of HBV-DNA and the expression level of HBsAg and HBeAg, which was similar to lamivudine, 3TC. The chemical structures of compounds 36~49 are shown in Figure 5. 2.5. Terpenoids Terpenes are a kind of compounds with isoprene as the basic structural unit. Terpenes have extensive biological activities, mainly including anti-inflammatory and antiviral effects [43]. Li et al. [19] isolated ursolic acid (50) from S. asper core material. Compound 50 had strong anti-HBV activity by inhibiting the production of HBsAg and HBeAg, with IC50 of 89.91 and 97.61 μM. A triterpenoid, named MH (51), was isolated from the Vicia tenuifolia Roth, which had significant inhibitory effect on the secretion of HBsAg and HBeAg in a dose-dependent manner [44]. Sweriyunnangenin A (52), 3-epitaraxerol (53), oleanolic acid (54), and erythrocentaurin (55), isolated from S. yunnanensis, could inhibit the secretion of HBsAg with IC50 values of 0.28, 0.70, and 1.26 mM, respectively. They also had good inhibitory effects on the secretion of HBeAg, with the IC50 values of 0.29, 1.41, and 0.94 mM, respectively. Especially, compound 55 could effectively inhibit the secretion of HBsAg and HBeAg, as well as the replication of HBV-DNA, due to its aldehyde group [26]. Zhou et al. [45] isolated a series of heptane terpenoids from the roots and rhizomes of Aster tataricus L. f. Among them, astataricusones B andepishionol (56-57) could inhibit the secretion of HBeAg, with IC50 value of 18.6 and 40.5 μM, and the replication HBV-DNA, with IC50 value of 2.7 and 30.7 μM. In addition, compound 56 had inhibitory effect on the secretion of HBsAg with IC50 value of 23.5 μM. Zhou et al. [46] carried out further research on A. tataricus, and 6 new shionane-type triterpenes were isolated. Among them, astershionones C (58) had good anti-HBV activity by inhibiting the secretion of HBsAg and HBeAg and the replication of HBV-DNA with IC50 values of 23.0, 23.1, and 22.4 μM, respectively. Bi et al. [47] found that 7 monoterpenes (4″-hydroxy-3″-methoxyalbiflorin (59), 6′-O-p-hydroxybenzoyl-4″-Hydroxyalbiflorin (60), albiflorin (61), oxypaeoniflorin (62), paeoniflorin (63),paeonins B (64), and benzoylpaeoniflorin (65)) of the Paeonia sinjiangensis K. Y. Pan had anti-HBV activity and could inhibit the secretion of HBsAg and HBeAg as well as the replication of HBV-DNA. Among them, compound 59 had the highest anti-HBV activity, which was even better than that of positive drug, 3TC. Perovskatone A and demethylsalvicanol (66-67), isolated from Perovskia atriplicifolia, had anti-HBV activity. It was for the first report on the anti-HBV effect of P. atriplicifolia [48]. Chrysanolide B-C and A (68-70) were isolated from Dendranthema indicum, and compound 70 had unknown trimer carbon skeleton. Compounds 68-70 had good anti-HBV activity on HepG 2.2.15 cell, and their anti-HBV activity was positively correlated with the degree of polymerization [49]. In the anti-HBV test, Pimelotides A (71) showed significant inhibition on the secretion of HBsAg, with an IC50 value of 0.016 g/mL and TI up to 355.63. However, the anti-HBV mechanism of compound 71 should be carried out for the further study [50]. Genkwanine P (73) and laurifolioside A (74), isolated from Wikstroemia chamaedaphne Meisn, exhibited potential antihepatitis B virus activities with IC50 values of 46.5 and 88.3 mg/mL, respectively. Wikstroelide W (72), 2-epi-laurifolioside A (75), laurifolioside B (76), 2-epi-laurifolioside B (77),laurifolioside (78), and 2-epi-laurifolioside (79) showed certain inhibitory effects on HBV-DNA replication with the inhibition ratios ranging from 2.0% to 33.0% at the concentrations ranging from 0.39 to 6.25 mg/mL [51]. It is reported that the extracts of Alternantheraphiloxeroides (Mart.) Griseb have antiviral properties in vitro. And oleanolic acid 3-O-β-D-glucuronopyranoside (80) and 4,5-dihydroblumenol (81), isolated from the extracts, showed significant inhibition against HepG2.2.15 cells transected with cloned HBV-DNA; their inhibitive ratios were 85.38% and 87.37% at 50 μg/mL, respectively [52]. Nine compounds 82-89 isolated from S. cincta, namely, swericinctosides A (82), swericinctoside B (83), 9-epi swertiamarin (84), 2′-O-m-hydroxybenzoyl swertiamarin (85), 4″-O-actyl swertianoside E (86), swertiaside (87), swertianoside C (88), and decentapicrin B (89), possessed inhibitory activity on HBV-DNA replication with IC50 values from 0.05 to 1.83 mM. Compounds 82, 84, and 86-88 showed moderate activity against HBsAg with IC50 values in the range of 0.24–2.46 mM, and compounds 82, 84, 87, and 88 could inhibit HBV-DNA replication with IC50 values of 0.30–0.62 mM. Compound 87 exhibited the most promising activity against HBV-DNA replication with an IC50 value of 0.05 mM (SI = 29.1), as well as moderate activity against the HBsAg secretion (IC50 = 0.79 mM) [53]. Geng et al. [54] found that the anti-HBV activity of erythrocentaurin (ET) derivatives was significantly improved. In particular, ET derivatives 1e and 1f (90, 91) showed the highest activity of inhibiting the replication of HBV-DNA, with IC50 values of 0.026 mM (SI > 70.8) and 0.045 mM (SI > 36.0), respectively. Swertiakoside A (92) and 2′-O-acetylswertiamarin (93) exhibited significant inhibitory activity on HBV-DNA replication with IC50values from 0.05 to 1.46 mmol·L−1 [38]. Huang et al. [55] isolated Asiaticoside (94) from Hydrocotyle sibthorpioides Lam and found that Asiaticoside could effectively inhibit the secretion of HBsAg and HBeAg. In addition, Asiaticoside could significantly reduce the transcription and replication of HBV-DNA by inhibiting the core, s1, s2, and x gene promoter activity. Liu et al. [56] found diosgenin (95) could effectively inhibit the secretion of HBsAg and HBeAg, with the inhibition rate reaching 40% and 50%. 7-Eudesm-4(15)-ene-1β,6α-diol (96) and Pumilaside A (97), isolated from Artemisia capillaris, exhibited promising activity against HBV-DNA replication with IC50 values of 19.70 and 12.01 μM, with high SI values of 105.5 and 139.2. In addition, compound 97 could also suppress the secretions of HBsAg and HBeAg with the IC50 values of 15.02 μM (SI = 111.3) and 9.00 μM (SI = 185.9) [57]. The chemical structures of compounds 50~97 showed in Figure 6. 2.6. Alkaloids Alkaloids, a kind of natural nitrogen heterocyclic, have complex ring structure, most of which have physiological activity [58]. Jiang et al. [59] found that the ethanol extract of Piper longum L. fruit had good anti-HBV effect, and erythro-1-[1-oxo-9(3,4-methylenedioxyphenyl)-8,9-dihydroxy-2E-nonenyl]-piperidine (98), threo-1-[1-oxo-9(3,4-methylenedioxyphenyl)-8,9-dihydroxy-2E-nonenyl]-piperidine (99), piperine (100), guineesine (101), and (2E,4E)-N-isobutyleicosa-2,4-dienamide (102) had significant inhibitory effect on the secretion of HBsAg and HBeAg on HepG 2.2.15 cells. 3β,4α-dihydroxy-1-(3-phenylpropanoyl)-piperidine-2-one (103), isolated from P. longum ethanol extract, had significant anti-HBV activity and could inhibit the secretion of HBsAg and HBeAg, with IC50 of 1.80 and 0.21 mM, respectively. The selectivity of compound 103 on HBeAg inhibition was up to 16.4, which was better than that of positive drug, 3TC, and has a good development prospect [60]. Zeng et al. [61] obtained a quaternary ammonium alkaloid DHCH (104) from Corydalis saxicola Bunting, which could significantly inhibit the secretion of HBsAg and HBeAg on HepG2.2.15 cells, with TI of 7.32 and 6.77, respectively. Further study showed that compound 104 could reduce the levels of cccDNA and DNA in dose and time dependence manner, with IC50 values of 15.08, 7.62, and 8.25 μM, respectively. The chemical structures of compounds 98~104 are shown in Figure 7. 2.7. Enediynes A. capillaris (Yin-Chen) is a famous traditional Chinese medicine (TCM) for treating acute and chronic hepatitis in China [62]. Geng et al. [63] isolated 14 compounds, 8S-deca-9-en-4,6-diyne-1,8-diol (105), (S)-deca-4,6,8-triyne-1,3-diol (106), (S)-3-hydroxyundeca-5,7,9-triynoic acid (107), 3S-Hydroxyundeca-5,9-triynoic acid 3-O-β-D-glucopyranoside (108), Atractylodin (109), Dendroarboreol B (110), Dehydrofalcarinol (111), Dehydrofalcarindiol (112), (E)-deca-2-en-4,10-diol (113), (Z)-deca-2-en-4,10-diol (114), 8-diol 1-O-β-D-glucopyranoside (115), 3S,8S-dihydroxydec-9-ene-4,6-diyne 1-O-β-D-glucopyranoside (116), 5-benzylthiophencarboxylic acid (117), and 2-methyl-6-phenyl-4H-pyran-4-one (118), from A. capillaris. All the compounds were assayed for their anti-HBV activity, and the structure-activity relationships were summarized based on the biological effects. In particular, compound 108 could significantly inhibit the secretions of HBsAg, HBeAg, and HBV-DNA replication with IC50 values of 197.2 (SI > 5.1), 48.7 (SI > 20.5), and 9.8 (SI > 102) μM. Hydroxyl and glycosyl groups are preferable for maintaining activity. In subsequent studies, Geng et al. [64] found that 3S,8S-dihydroxydec-9-en-4,6-yne 1-O-(6′-O-caffeoyl)-β-D-glucopyranoside and 3S,8S-dihydroxydec-9-en-4,6-yne 1-O-(2′-O-caffeoyl)-β-D-glucopyranoside (119-120) had the activity against the secretions of HBsAg and HBeAg and HBV DNA replication. Especially, compounds 119 and 120 inhibited HBV-DNA replication with IC50 values of 0.077 ± 0.04 and 0.0127 ± 0.05 mM, with SI values of 23.6 and 17.1, respectively. Compounds 119 and 120 as a pair of isomers showed similar inhibition on HBsAg secretion with IC50 values of 0.797 ± 0.23 mM (SI = 2.1) and 0.887 ± 0.20 mM (SI =2.3), but no activity against HBeAg secretion. Compound 119 displayed the highest inhibitory activity on HBV-DNA replication with an IC50 value of 0.077 ± 0.04 mM (SI = 23.6), and compound 120 showed slightly decreased activity with an IC50 value of 0.127 ± 0.05 mM (SI = 17.1). The above analyses suggested that the caffeoyl group played important role in maintaining the anti-HBV activity but the substitution position may not be crucial. The chemical structures of compounds 105~120 are shown in Figure 8. 2.8. Aromatics Six phenols, m-hydroxybenzoic acid (121), p-hydroxybenzoic acid (122), m-hydroxy benzenmethanol (123), 3,4-dihydroxybenzoic acid (124), ethyl 3,4-dihydroxybenzoate (125), and ethyl 2,5-dihydroxybenzoate (126), exhibited anti-HBV activities by inhibiting HBsAg and HBeAg secretion with IC50 values from 0.23 to 5.18 mM, and HBV-DNA replication with IC50 values from 0.06 to 2.62 mM. Compounds 121-123, with one hydroxyl and one carboxyl, showed anti-HBV activity with IC50 values of 3.76, 5.18, and 4.55 mM for inhibitory HBsAg secretion and 2.36, 2.54, and 2.62 mM for inhibitory HBV-DNA replication, respectively. Compounds 124-126 with two hydroxyls and one carboxyl displayed remarkable inhibition on HBV-DNA replication with IC50 values of <0.06, 0.22, and 0.29 mM. Furthermore, compounds 125 and 126 showed significant inhibitory effect on the secretion of HBsAg (IC50 = 0.14 and 0.23 mM) and HBeAg (IC50 = 5.03 and 3.74 mM) [34]. 3,3′,5-Trihydroxybiphenyl (127), isolated from S. chirayita, showed activity against HBeAg secretion with IC 50 values of 0.77 ± 0.076 and 5.92 ± 1.02 mM [27]. Taraffinisoside A (128), descaffeoyl crenatoside (129), and 3,4-dihydroxyphenylethanol-8-O-[β-D-apiofuranosyl (1 → 3)]-β-D-glucopyranoside (130) isolated from Tarphochlamys affinis (Griff.) could inhibit the secretion of HBsAg and HBeAg [65]. Huang et al. [66] isolated p-hydroxy acetophenone (PHAP) (131) from A. morrisonensis, which could significantly inhibit the replication of HBV. The mechanism may be that PHAP was involved in regulating the expression of surface protein genes and blocks the release of virus particles by interfering with the signaling pathway of endoplasmic reticulum. Zhao et al. [67] found that PHAP and derivatives have good anti-HBV activity, and structural modification on p-HAP and its glycoside led to a series of derivatives; among them, p-HAP derivative 2f (132) had the strongest effect on inhibiting the replication HBV-DNA (IC50 = 5.8 μM, SI = 160.3). The primary structure-activity relationships suggested that the conjugated derivatives of p-HAP glycoside and substituted cinnamic acids obviously enhanced the activity against HBV-DNA replication. The chemical structures of compounds 121~132 are shown in Figure 9. 2.9. Phenylalanine Dipeptides Yang et al. [68] isolated and modified the phenylalanine dipeptide Matijin-Su (133) with anti-HBV activity from Dichondra repens Forst, and four derivatives were screened with anti-HBV activity in vitro. Yang et al. [69] found that compound 101 could inhibit the replication of HBV-DNA, with IC50 value of 1.33 μM, and inhibit the replication of various mutant HBV strains. Xu et al. [70] synthesized a series of MTS derivatives with anti-HBV activity by the design of the Matijin-Su (MTS). One of the preferred MTS derivatives (Y101) was conducted in the clinical preclinical study and received the clinical approval of the CFDA. Kuang et al. [71] used the compound MTS as lead compound; a novel MTS derivative was designed and synthesized by introducing the structure unit of veratrol acid; N-[N-(3,4-dimethoxy-benzoyl)-L-phenylalanyl]-O-propionyl-L-phenylalaninol (134), N-[N-(3,4-dimethoxy-benzoyl)-L-phenylalanyl]-4-ethoxy-L-phenylalaninol (135), and N-[N-(3,4-Dimethoxy-benzoyl)-L-phenylalanyl]-4-ethoxycarbonylmethyl-L-tyrosinol (136) were tested the anti-HBV activity in vitro. All the compounds have the significant anti-HBV activity. Subsequently, a series of MTS derivatives were designed and synthesized with compound MTS as the lead compound, by introducing fluorine or chlorine substitution, and the obtained MTS derivatives were tested for anti-HBV activity in vitro. N-[N-(4-chlorobenzoyl)-O-methyl-L-tyrosyl]-L-Phenylalaninol (137), N-[N-(4-chlorobenzoyl)-O-propyl-L-tyrosyl]-L-Phenylalaninol (138), and N-[N-(4-chlorobenzoyl)-O-isopropyl-L-tyrosyl]-L-Phenylalaninol (139) showed good anti-HBV activity, with IC50 of 12.61, 10.53, and 6.46 mol/L, respectively [72]. Cui et al. [73] synthesized 20 MTS derivatives containing trifluoromethyl substitution and tested the anti-HBV activity of the synthesized target compound in HepG 2.2.15 cells in vitro. Among them, N-[N-(3-trifluoromethylbenzoyl)-L-tyrosyl]-L-Phenylalaninol (140), N-[N-(3-trifluoromethylbenzoyl)-L-phenylalanyl]-O-propionyl-L-tyrosine methyl ester (141), and N-[N-(3-trifluoromethylbenzoyl)-L-phenylalanyl]-O-ethyl-L-tyrosine (142) showed strong anti-HBV activity, and their IC50 reached 11.74, 8.73, and 11.41 mol·L−1. Jang et al. [74] synthesized twenty novel n-methyl derivatives of MTS, among which compounds 8n (143) and 8o (144) showed certain anti-HBV activity, with IC50 of 52.5 mol·L−1 and 49.2 mol·L−1, respectively. Compounds 9 a-c(145-147) were triantennary cluster galactosides of MTS with potential for hepatic targeting. The anti-HBV activities of those were evaluated in HepG 2.2.15 cells. And all those compounds had inhibitory effect on HBV-DNA replication in HepG2 2.2.15 cells in a dose-response manner [75]. Huang et al. [76] evaluated the 20 species of marine natural small molecule compounds by HepG 2.2.15 cell lines; three kinds of compounds cyclic (glycine-L-proline) (148), cyclic (4-hydroxy proline-phenylalanine) (149), and cyclic (L-2-hydroxy proline-phenylalanine) (150) had anti-HBV activity on the inhibition of HBsAg, HBeAg, and HBV-DNA, with the treatment of index greater than 2. N-acetyl phenylalanine (151) had certain inhibitory effects on HBsAg and HBeAg with the IC50 values of 55.5, 69.5 μg/mL, respectively [77]. The chemical structures of compounds 133-151 are shown in Figure 10. 2.10. Others 2.10.1. Lactones Two dimers of oxanthrone andiridoid lactone (152, 153) were isolated from S. punicea, which could inhibit the secretion of HBsAg with IC50 value of 0.25 and 0.29 mM, and the secretion of HBeAg with IC50 value of 0.86 and 0.31 mM. In addition, compounds 152-153 also could inhibit the replication of HBV-DNA, with the IC50 values of 0.18 and 0.19 mM, respectively [78]. Anislactone B (154), a kind of nor sesquiterpene lactone with unique structure from the fruit of Illicium henryi, had high anti-HBV activity and could inhibit the secretion of HBeAg on HepG 2.2.15 cell with IC500.079 ± 0.035 mMin vitro [79]. 2.10.2. Isosteviol The analogue of isosteviol, NC-8 (155), had anti-HBV activity by inhibiting the secretion of HBsAg and HBeAg, with the IC50 value of 7.89 g/mL, which was better than that of the positive control (lamivudine). The mechanism of NC-8 was interfering with HBV replication and gene expression and blocking the TLR2/NF-κb signaling pathway of host cells. It is for the first report of isosteviol analogues against HBV [80]. Huang et al. [81] got a series of new derivatives, including the IN-4 (156) with high anti-HBV activity. The mechanism might be that IN-4 suppressed the expression of HBV gene and the replication of HBV-DNA by interfering with the NF-κB signaling pathways of host cell. 2.10.3. Organic Acids Scoparamide A (157) could inhibit not only the secretions of HBsAg and HBeAg with IC50 values of 0.617 ± 0.25 mM (SI = 2.1) and 0.887 ± 0.25 mM (SI = 1.4), respectively, but also HBV-DNA replication with an IC50 value of 0.477 ± 0.14 mM (SI = 2.7) [64]. Zhang et al. [82] isolated cichoric acid (158) from the leaves of Chicory intybus L and found that it had significant anti-HBV activity. Rosmarinic acid (159) inhibits HBV replication in HBV-infected cells by specifically targeting ε-Pol binding. In addition, they analyzed an additional 25 rosmarinic acid derivatives and found that the “two phenolic hydroxyl groups at both ends” and the “caffeic acid-like structure” of rosmarinic acid are critical for the inhibition of ε-Pol binding [83]. It is well known that phenolic acids have better antiviral activity. The studies showed that 3-caffeoylquinicacid (160) [84] could inhibit the secretion of HBsAg, HBeAg, and the replication of HBV-DNA on Hep G 2.2.15 cells at the concentration of 100 μg/mL. In order to reveal the anti-HBV activity and structure-activity relationships of the analogues of chlorogenic acid, 9 chlorogenic acid analogues were evaluated on HepG 2.2.15 cell lines in vitro and found that chlorogenic acid, cryptochlorogenic acid (161), neochlorogenic acid (162), 3,5-dicaffeoylquinic acid (163), 4,5-dicaffeoylquinic acid (164), and 3,4-dicaffeoylquinic acid (165) possessed potent activity against HBV-DNA replication with IC50 values in the range of 5.5 ± 0.9-13.7 ± 1.3 μM. Di-caffeoyl analogues (163-165) also exhibited activity against the secretions of HBsAg and HBeAg. The number of caffeoyl moiety may contribute to the inhibitory activity against HBsAg and HBeAg secretions, while the position of caffeoyl units play little role on anti-HBV-DNA activities. In addition, carboxyl group is closely associated to the antiviral activity [85]. The chemical structures of compounds 152~165 are shown in Figure 11. 2.10.4. Polysaccharides Natural polysaccharide is mainly referred to widely exists in the nature of cellulose and its derivatives, chitin, and other natural polymer materials. Polysaccharides have a wide range of biological activities, such as enhanced immunity, antiviral, and anti-inflammatory [86, 87]. In recent years, clinical researches of natural polysaccharides on anti-HBV have increased gradually; they have been proved to have significant anti-HBV effect [88]. Lentinan polysaccharide has a prominent effect on antiviral and immune regulation and is also used as an auxiliary drug for cancer and HBV [89, 90]. Zhao et al. [91] obtain two polysaccharide fractions (LEP-1 and LEP-2) from Lentinus edodes (Berk.) sing. They found that LEPs possess potent anti-HBV activity in vitro. In addition, the polysaccharides from Hedyotis caudatifolia Merr.et Metcalf (50, 100, and 200 mg/L) significantly inhibited the secretion and expression of HBV-DNA on HepG 2.2.15 cells and effectively inhibited the secretion of HBsAg and HBeAg. Its mechanism may be related to the activation of JAK/STAT signaling pathway and the promotion of antiviral protein expression [92]. Zhan et al. [93] found that snail polysaccharides have a certain inhibitory effect on the replication of HBV-DNA (P < 0.01), which indicated that the maximum inhibition rate of HBsAg and HBeAg in HepG 2.2.15 cells is 42.8% and 52.1%, respectively, slightly below the positive control group (P < 0.05), and the inhibition effect of snail polysaccharide on HBeAg was better than that of HBsAg. The results of real-time fluorescence quantitative PCR test showed that snail polysaccharide had a certain inhibitory effect on the replication of HBV-DNA (P < 0.011). The anti-HBV effect of polyporus polysaccharide may be related to the regulation of the body's immune function, breaking the body's immune tolerance or low state [94]. Angelica sinensis polysaccharide [95] could promote DC mature of HBV transgenic mice, raise its coordinated stimulus molecules on the surface, enhance its promoting lymphocyte proliferation and secretion, strengthen its antigen oral ability, induce cellular immune response, reduce serum concentrations of HBsAg, and play a role in antiviral immunity. Liu et al. [96] extracted Chinese whelk polysaccharide by water extraction and transfected human hepatocellular carcinoma cells with HBV-DNA cloning as an experimental model. The results showed that PCC significantly inhibited HBV-DNA in HepG 2.2.15 cells at 0.1 mg·mL−1 and 1 mg·mL−1. Xia et al. [97] investigated the effect of polysaccharides of Sipunculus nudus Linnaeus on anti-HBV; the results showed that polysaccharide with different dose groups were different degree of inhibition of HBV-DNA replication (P < 0.05), and the effects of high, middle dose group were similar to acyclovir. 3. Conclusion and Perspectives At present, a variety of natural products with novel structure and high anti-HBV activity were isolated from natural resources. Among them, we found that terpenoids with antihepatitis B activity are the most (Figure 6 and Table 1), and the activity is more significant. However, the research content were disorderly and mainly focus on the simple isolation and identification of anti-HBV activity ingredients; the in-depth studies of anti-HBV mechanisms and targets are relatively rare. Moreover, most of the studies are limited to cell level, lack of animal model experiments, and no in-depth research of ingredients with significant antihepatitis B activity. Therefore, there are three suggestions for product research and development: 3.1. Search for New Natural Product Resources The research on natural products against hepatitis B mainly focuses on the field of traditional Chinese medicine on land. The research on traditional Chinese medicine against hepatitis b has been very matured. However, it is still difficult to develop active natural products against HBV. In addition, there are few researches on marine natural products, microbial fermentation products, plant polysaccharides, and other aspects. In recent years, studies have found that marine natural products have good biological activity due to their special growth environment. Huang et al. [76] screened significant anti-HBV active ingredients from small marine molecules. Microbial fermentation products are a novel source of natural products. In recent years, many novel compounds are derived from microbial fermentation products. It is an interesting way to study the anti-HBV activity of microbial fermentation products. Plant polysaccharides have a wide range of biological activities, and studies [88–95] have shown that the chemical components of polysaccharides have a good anti-HBV activity. It is of great significance to search for anti-HBV active ingredients from novel natural products. 3.2. Novel Method for Screening The traditional screening of anti-HBV activity involves the separation and identification of chemical components in traditional Chinese medicinal materials and then the screening of their activity, which often takes time and effort and is difficult to obtain accurate screening results. In recent years, researchers used computer-aided drug design (molecular simulation docking) to screen out suitable compounds from the database and then carried out screening in vitro. This method has strong purpose and high accuracy. A series of derivatives with good anti-HBV activity were obtained by modifying the structure of known compounds with anti-HBV activity, and the derivatives with the best activity were screened out through activity test. This method also provides a new idea for discovering anti-HBV compounds with better activity [71–75]. 3.3. Synergy Effect Single-chemical components of natural products are no longer effective against HBV, and drug resistance will appear. For example, artemisinin is combined with other components to fight malaria. In anti-HBV studies, treatment methods of combination drugs are also widely used [98]. Acknowledgments This work was supported by the Key Project in Science and Technology of Henan Province (182102410083). Data Availability The data used to support the findings of this study are available from the corresponding author upon request. Conflicts of Interest The authors declare no conflict of interest. Authors' Contributions All authors contributed to the manuscript. W.K. and Z.L. conceived this subject. X.L. and C.M. searched, collected, and analyzed the relevant literature, as well as prepared the first draft. W.K. and X.L. critically read and revised the paper. All authors read and approved the final manuscript. Figure 1 HBV life cycle and therapeutic targets. HBV life cycle: adsorption, penetration, biosynthesis, assembly, and secretion; therapeutic targets: entry inhibitors (NTCP and HSPG as the receptor-virus binding), cccDNA inhibitors (inhibiting the information of cccDNA), Epi-drugs (inhibiting the viral RNA synthesis), endoplasmic reticulum inhibitors (inhibiting the viral capsid assembly), and glucosidese inhibitors (inhibiting the secretion of HBV proteins). Figure 2 Chemical structures of representative anti-HBV phenylpropanoids 1-14. Figure 3 Chemical structures of representative anti-HBV flavonoids 15-22. Figure 4 Chemical structures of representative anti-HBV xanthones 23-35. Figure 5 Chemical structures of representative anti-HBV anthroquinones 36-49. Figure 6 Chemical structures of representative anti-HBV terpenes 50-97. Figure 7 Chemical structures of representative anti-HBV alkaloids 98-104. Figure 8 Chemical structures of representative anti-HBV enediynes 105-120. Figure 9 Chemical structures of representative anti-HB Varomatics 121-132. Figure 10 Chemical structures of representative anti-HBV phenylalanine dipeptides 133-151. Figure 11 Chemical structures of representative anti-HBV compounds 152-165. Table 1 The compounds with anti-HBV effects from natural products. No. Compound Target Source Ref 1 6-Hydroxyl-7-methoxyl-coumarin HBsAg and HBeAg S. asper [19] 2 Esculetin HBsAg, HBeAg, and HBV-DNA M. fortunei [20] 3 Magnatriol B HBsAg and HBeAg S. asper [21] 4 Honokiol HBsAg and HBeAg S. asper [21] 5 Isomagnolol HBsAg S. asper [22, 23] 6 isocarpine HBsAg S. asper [22, 23] 7 Honokiol S. asper [22, 23] 8 (7′R, 8′S, 7′R, 8′S)-erythron-Strebluslignanol G HBsAg, HBeAg, and HBV-DNA S. asper [22, 23] 9 Coumarin lignan HBsAg and HBeAg K. heteroclita [24] 10 Niranthin HBsAg and HBeAg P. niruri [25] 11 (+)-Dehydrod-iconiferyl alcohol HBsAg S. patens [26] 12 Dehydrozingerone HBsAg S. patens [26] 13 (+)-Cycloolivil-4′-O-β-D-glucopyranoside HBsAg, HBeAg, and HBV-DNA S. chirayita [27] 14 Syringaresinol 4-O-β-D-glucopyranoside HBsAg S. chirayita [27] 15 Luteolin HBsAg and HBeAg S. macrosperma [29] 16 Isovitexin HBsAg, HBeAg, and HBV-DNA S. yunnanensis [30] 17 LPRP-Et-97543 Core, S, and preS promoters L. muscari [31] 18 Quercetin HBeAg [32] 19 Glabaarachalcone HBV-DNA P. pinnata [33] 20 Isopongachromene HBV-DNA P. pinnata [33] 21 Isooriention HBsAg, HBeAg, and HBV-DNA S. mussotii [34] 22 Epimedium Hyde II HBsAg, HBeAg, and HBV-DNA [35] 23 Norbellidifolin HBV-DNA S. mussotii [36] 24 1,5,8-Trihydroxy-3-methoxyxanthone HBsAg and HBeAg S. mussotii [36] 25 2-C-β-D-glucopyranosyl-1,3,7-trihydroxyxanthone HBsAg and HBeAg S. mussotii [36] 26 Norswertianolin HBV-DNA S. mussotii [36] 27 Norswertianin-1-O-β-D-glucoside HBV-DNA S. mussotii [36] 28 1,7-Dihydroxy-3,8-dimethoxyxanthone HBV-DNA S. mussotii [36] 29 7-O-[β-D-xylopyranosyl-(1→2)-β-D-xylopyranosyl]-1,8-dihydroxy-3-methoxyxanthone HBV-DNA S. mussotii [36] 30 Mangiferin HBV-DNA S. mussotii [36] 31 Methyl6,8-dihydroxy-3-methyl-9-oxo-9H-xanthene-1-carboxylate HBsAg Penicillium sp. [37] 32 1,8-Dihydroxy-3,5-dimethoxyxanthone HBsAg, HBeAg, and HBV-DNA S. yunnanensis [30] 33 Norswertianolin HBV-DNA S. yunnanensis [30] 34 Neolancerin HBsAg, HBeAg, and HBV-DNA S. yunnanensis [30] 35 1,5,8-Trihydroxy-3-methoxyxanthone HBeAg and HBV-DNA S. delavayi [38] 36 (−)-2′R-1-hydroxyisorhodoptilometrin HBsAg and HBeAg Penicillium sp. [37] 37 Asterric acid HBsAg Penicillium sp. [37] 38 Questinol HBsAg Penicillium sp. [37] 39 Endocrocin HBsAg Penicillium sp. [37] 40 (+)-2′S-isorhodoptilometrin HBsAg Penicillium sp. [37] 41 Sulochrin HBsAg Penicillium sp. [37] 42 Monochlorsulochrin HBsAg and HBeAg Penicillium sp. [37] 43 Dihydrogeodin HBsAg Penicillium sp. [37] 44 1,3-Dihydroxy-2-hydroxymethyl-9,10-anthraquinone HBeAg and HBsAg P. connata [40] 45 Rubiadin HBeAg, HBsAg, HBx, and HBV-DNA P. connata [40] 46 Anthraquinone bile acid conjugates HBeAg and HBsAg P. connata [40] 47 Aloin B HBV-DNA polymerase Aloe vera [41] 48 Aloe-emodin CYP3A4 Aloe vera [41] 49 Hypericin HBsAg, HBeAg, HBV-DNA, and pgRNA [42] 50 Ursolic acid HBsAg and HBeAg S. asper [19] 51 MH HBsAg and HBeAg V. tenuifolia [44] 52 Sweriyunnangenin A HBsAg and HBeAg S. yunnanensis [26] 53 3-Epitaraxerol HBsAg and HBeAg S. yunnanensis [26] 54 Oleanolic acid HBsAg and HBeAg S. yunnanensis [26] 55 Erythrocentaurin HBsAg, HBeAg, and HBV-DNA S. yunnanensis [26] 56 Astataricusones B HBeAg, HBV-DNA, and HBsAg A. tataricus [45] 57 Epishionol HBeAg and HBV-DNA A. tataricus [45] 58 Astershionones C HBsAg, HBeAg, and HBV-DNA A. tataricus [46] 59 4″-Hydrox″y-3″-methoxyalbiflorin HBsAg, HBeAg, and HBV-DNA P. sinjiangensis [47] 60 6′-O-p-hydroxybenzoyl-4″-Hydroxyalbiflorin HBsAg, HBeAg, and HBV-DNA P. sinjiangensis [47] 61 Albiflorin HBsAg, HBeAg, and HBV-DNA P. sinjiangensis [47] 62 Oxypaeoniflorin HBsAg, HBeAg, and HBV-DNA P. sinjiangensis [47] 63 Paeoniflorin HBsAg, HBeAg, and HBV-DNA P. sinjiangensis [47] 64 Paeonins B HBsAg, HBeAg, and HBV-DNA P. sinjiangensis [47] 65 Benzoylpaeoniflorin HBsAg, HBeAg, and HBV-DNA P. sinjiangensis [47] 66 Perovskatone A HBsAg P. atriplicifolia [48] 67 Demethylsalvicanol HBsAg P. atriplicifolia [48] 68 Chrysanolide B HBsAg and HBeAg D. indicum [49] 69 Chrysanolide C HBsAg and HBeAg D. indicum [49] 70 Chrysanolide A HBsAg and HBeAg D. indicum [49] 71 Pimelotide A HBsAg P. elongata foliage [50] 72 Wikstroelide W HBV-DNA W. chamaedaphne [51] 73 Genkwanine P W. chamaedaphne [51] 74 laurifolioside A W. chamaedaphne [51] 75 2-Epi-laurifolioside A HBV-DNA W. chamaedaphne [51] 76 Laurifolioside B HBV-DNA W. chamaedaphne [51] 77 2-Epi-laurifolioside B HBV-DNA W. chamaedaphne [51] 78 Laurifolioside HBV-DNA W. chamaedaphne [51] 79 2-epi-laurifolioside HBV-DNA W. chamaedaphne [51] 80 Oleanolic acid 3-O-β-D-glucuronopyranoside HBV-DNA A.philoxeroides [52] 81 4,5-Dihydroblumenol HBV-DNA A.philoxeroides [52] 82 Swericinctosides A HBV-DNA and HBsAg S. cincta [53] 83 Swericinctoside B HBV-DNA S. cincta [53] 84 9-Epi swertiamarin HBV-DNA and HBsAg S. cincta [53] 85 2′-O-m-hydroxybenzoyl swertiamarin HBV-DNA S. cincta [53] 86 4″-O-actyl swertianoside E HBV-DNA and HBsAg S. cincta [53] 87 Swertiaside HBV-DNA and HBsAg S. cincta [53] 88 Swertianoside C HBV-DNA and HBsAg S. cincta [53] 89 Decentapicrin B HBV-DNA S. cincta [53] 90 ET derivatives 1e HBV-DNA Synthesis [54] 91 ET derivatives 1f HBV-DNA Synthesis [54] 92 Swertiakoside A HBV-DNA S. delavayi [38] 93 2′-O-acetylswertiamarin HBV-DNA S. delavayi [38] 94 Asiaticoside HBsAg, HBeAg, and HBV-DNA H. sibthorpioides [55] 95 Diosgenin HBsAg and HBeAg [56] 96 7-Eudesm-4(15)-ene-1β,6α-diol HBV-DNA A. capillaris [57] 97 Pumilaside A HBeAg, HBsAg, and HBV-DNA A. capillaris [57] 98 Erythro-1-[1-oxo-9(3,4-methylenedioxyphenyl)-8,9-dihydroxy-2E-nonenyl]-piperidine HBsAg and HBeAg P. longum [59] 99 Threo-1-[1-oxo-9(3,4-methylenedioxyphenyl)-8,9-dihydroxy-2E-nonenyl]-piperidine HBsAg and HBeAg P. longum [59] 100 Piperine HBsAg and HBeAg P. longum [59] 101 Guineesine HBsAg and HBeAg P. longum [59] 102 (2E,4E)-N-isobutyleicosa-2,4-dienamide HBsAg and HBeAg P. longum [59] 103 3β,4α-dihydroxy-1-(3-phenylpropanoyl)-piperidine-2-one HBsAg and HBeAg P. longum [60] 104 DHCH HBsAg, HBeAg, cccDNA, and DNA C. saxicola [61] 105 8S-deca-9-en-4,6-diyne-1,8-diol HBsAg, HBeAg, and HBV-DNA A. capillaris [63] 106 (S)-deca-4,6,8-triyne-1,3-diol HBsAg, HBeAg, and HBV-DNA A. capillaris [63] 107 (S)-3-hydroxyundeca-5,7,9-triynoic acid HBsAg, HBeAg, and HBV-DNA A. capillaris [63] 108 3S-Hydroxyundeca-5,9-triynoic acid 3-O-β-D-glucopyranoside HBsAg, HBeAg, and HBV-DNA A. capillaris [63] 109 Atractylodin HBsAg, HBeAg, and HBV-DNA A. capillaris [63] 110 Dendroarboreol B HBsAg, HBeAg, and HBV-DNA A. capillaris [63] 111 Dehydrofalcarinol HBsAg, HBeAg, and HBV-DNA A. capillaris [63] 112 Dehydrofalcarindiol HBsAg, HBeAg, and HBV-DNA A. capillaris [63] 113 (E)-deca-2-en-4,10-diol HBsAg, HBeAg, and HBV-DNA A. capillaris [63] 114 (Z)-deca-2-en-4,10-diol HBsAg, HBeAg, and HBV-DNA A. capillaris [63] 115 8-Diol 1-O-β-D-glucopyranoside HBsAg, HBeAg, and HBV-DNA A. capillaris [63] 116 3S,8S-dihydroxydec-9-ene-4,6-diyne1-O-β-D-glucopyranoside HBsAg, HBeAg, and HBV-DNA A. capillaris [63] 117 5-Benzylthiophencarboxylic acid HBsAg, HBeAg, and HBV-DNA A. capillaris [63] 118 2-Methyl-6-phenyl-4H-pyran-4-one HBsAg, HBeAg, and HBV-DNA A. capillaris [63] 119 3S,8S-dihydroxydec-9-en-4,6-yne 1-O-(6′-O-caffeoyl)-β-D-glucopyranoside HBsAg, HBeAg, and HBV-DNA A. capillaris [64] 120 3S,8S-dihydroxydec-9-en-4,6-yne1-O-(2′-O-caff-eoyl)-β-D-glucopyranoside HBsAg, HBeAg, and HBV-DNA A. capillaris [64] 121 m-Hydroxybenzoic acid HBsAg, HBeAg, and HBV-DNA S. mussotii [34] 122 p-Hydroxybenzoic acid HBsAg, HBeAg, and HBV-DNA S. mussotii [34] 123 m-Hydroxy benzenmethanol HBsAg, HBeAg, and HBV-DNA S. mussotii [34] 124 3,4-Dihydroxybenzoic acid HBsAg, HBeAg, and HBV-DNA S. mussotii [34] 125 Ethyl 3,4-dihydroxybenzoate HBsAg, HBeAg, and HBV-DNA S. mussotii [34] 126 Ethyl 2,5-dihydroxybenzoate HBsAg, HBeAg, and HBV-DNA S. mussotii [34] 127 3,3′,5-Trihydroxybiphenyl HBeAg S. chirayita [27] 128 TaraffinisosideA HBsAg and HBeAg T. affinis [65] 129 Descaffeoyl crenatoside HBsAg and HBeAg T. affinis [65] 130 3,4-Dihydroxyphenylethanol-8-O-[β-D-apiofuranosyl (1→3)]-β-D-glucopyranoside HBsAg and HBeAg T. affinis [65] 131 p-Hydroxy acetophenone (PHAP) HBsAg A. morrisonensis [66] 132 p-HAP derivative 2f HBV-DNA A. capillaris [67] 133 Matijin-Su HBV-DNA D. repens [68] 134 N-[N-(3,4-dimethoxy-benzoyl)-L-phenylalanyl]-O-propionyl-L-phenylalaninol HBV-DNA Synthesis [71] 135 N-[N-(3,4-dimethoxy-benzoyl)-L-phenylalanyl]-4-ethoxy-L-phenylalaninol HBV-DNA Synthesis [71] 136 N-[N-(3,4-Dimethoxy-benzoyl)-L-phenylalanyl]-4-ethoxycarbonylmethyl-L-tyrosinol HBV-DNA Synthesis [71] 137 N-[N-(4-chlorobenzoyl)-O-methyl-L-tyrosyl]-L-Phenylalaninol HBV-DNA Synthesis [72] 138 N-[N-(4-chlorobenzoyl)-O-propyl-L-tyrosyl]-L-Phenylalaninol HBV-DNA Synthesis [72] 139 N-[N-(4-chlorobenzoyl)-O-isopropyl-L-tyrosyl]-L-Phenylalaninol HBV-DNA Synthesis [72] 140 N-[N-(3-trifluoromethylbenzoyl)-L-tyrosyl]-L-Phenylalaninol HBV-DNA Synthesis [73] 141 N-[N-(3-trifluoromethylbenzoyl)-L-phenylalanyl]-O-propionyl-L-tyrosine methyl ester HBV-DNA Synthesis [73] 142 N-[N-(3-trifluoromethylbenzoyl)-L-phenylalanyl]-O-ethyl-L-tyrosine HBV-DNA Synthesis [73] 143 Compound 8n HBV-DNA Synthesis [74] 144 Compound 8o HBV-DNA Synthesis [74] 145 Compound 9 a HBV-DNA Synthesis [75] 146 Compound 9 b HBV-DNA Synthesis [75] 147 Compound 9 c HBV-DNA Synthesis [75] 148 Cyclic (glycine-L-proline) HBsAg, HBeAg, and HBV-DNA [76] 149 Cyclic (4-hydroxy proline-phenylalanine) HBsAg, HBeAg, and HBV-DNA [76] 150 Cyclic (L-2-hydroxy proline-phenylalanine) HBsAg, HBeAg, and HBV-DNA [76] 151 N-acetyl phenylalanine HBsAg and HBeAg P. crinitum [77] 152 Two dimers of oxanthrone HBsAg, HBeAg, and HBV-DNA S. punicea [78] 153 Iridoid lactone HBsAg, HBeAg, and HBV-DNA S. punicea [78] 154 Anislactone B HBeAg I. henryi [79] 155 NC-8 HBsAg and HBeAg Synthesis [80] 156 IN-4 HBV-DNA Synthesis [81] 157 Scoparamide A HBsAg, HBeAg, and HBV-DNA A. scoparia [64] 158 Cichoric acid DHBV-DNA C. intybus [82] 159 Rosmarinic acid ε-Pol binding [83] 160 3-Caffeoylquinicacid HBsAg, HBeAg, and HBV-DNA L. japonica [84] 161 Cryptochlorogenic acid HBV-DNA L. japonica [84] 162 Neochlorogenic acid HBV-DNA L. japonica [84] 163 3,5-Dicaffeoylquinic acid HBsAg, HBeAg, and HBV-DNA L. japonica [84] 164 4,5-Dicaffeoylquinic acid HBsAg, HBeAg, and HBV-DNA L. japonica [84] 165 3,4-Dicaffeoylquinic acid HBsAg, HBeAg, and HBV-DNA L. japonica [84] ==== Refs 1 Wohlfarth C. Efferth T. Natural products as promising drug candidates for the treatment of hepatitis B and C Acta Pharmacologica Sinica 2009 30 1 25 30 10.1038/aps.2008.5 2-s2.0-64849111443 19060918 2 Safioleas M. Lygidakis N. J. Manti C. Hepatitis B today Hepato-Gastroenterology 2007 54 74 545 548 17523319 3 World Health Organisation Hepatitis B, factsheet, No.204 2014 https://www.who.int/Mediacentre/factsheets/fs204/en/1 4 Mason W. S. Cancer Associated Viruses 2012 New York Springer-Verlag New York Inc. 5 Nassal M. New insights into HBV replication: new opportunities for improved therapies Future Virology 2009 4 1 55 70 10.2217/17460794.4.1.55 2-s2.0-70349215530 6 Li Y. T. Huang J. W. Xu R. A. Cui X. L. Progress in recent study of anti-HBV natural products and extracts Mini-reviews in Organic Chemistry 2013 10 3 241 253 10.2174/1570193X11310030004 2-s2.0-84882788712 7 Cai M. Z. Qin G. Research advances in anti-hepatitis B virus drugs Clinical Gastroenterology and Hepatology 2019 35 10 2302 2307 8 Xu Z. C. Zhao K. T. Jiang Y. A. Development of antiviral drugs against hepatitis B virus (in Chinese) Chinese Science Bulletin 2019 64 3123 3141 9 Ahmed H. Arbab M. K. P. Mohammed S. A. D. Adnan J. A. R. In vitro evaluation of novel antiviral activities of 60 medicinal plants extracts against hepatitis B virus Experimental and Therapeutic Medicine 2017 14 626 634 28672977 10 Duan Z. H. Chen X. M. Research progress on the active constituents of Chinese traditional medicine for anti HBV Journal of Liaoning University 2016 18 11 112 115 11 Yao X. C. Xiao X. Huang B. K. Xu Z. Y. Molecular docking and in vitro screening of active anti-hepatitis B virus components from Abrus cantoniensis The Chinese Journal of Clinical Pharmacology 2019 35 5 439 441 12 Li Y. T. Xu R. A. Cui X. L. Progress in anti-hepatitis B virus natural drugs targeting different sites Chinese Journal of Pharmacology and Toxicology 2012 26 5 702 705 13 Tong S. P. Li J. S. Wands J. R. Affecting B virus genetic conventions: biological properties and clinical implications Emerging Microbes and Infections 2019 2 3 1 11 14 Wang Y. L. Wang R. X. Hou W. B. Anti-viral components of natural products Natural Product Research and Development 2007 19 179 182 15 Chen J. Wu J. M. Advances in the structure and function of HBV open reading frame International Journal of Digestive Diseases 2008 28 2 114 116 16 Grimm D. Thimme R. Blum H. E. HBV life cycle and novel drug targets Hepatology International 2011 5 2 644 653 10.1007/s12072-011-9261-3 2-s2.0-79956271873 21484123 17 Urban S. Schulze A. Dandri M. The replication cycle of hepatitis B virus Journal of Hepatology 2010 52 2 282 284 10.1016/j.jhep.2009.10.031 2-s2.0-75349095571 20056291 18 Hu D. Wei G. W. Qu Z. Y. Research progress on hepatoprotective effects of Schissandra chinensis Journal of Pharmaceutical Research 2019 38 4 229 232 19 Li L. Q. Li J. Huang Y. Lignans from the heartwood of Streblus asper and their inhibiting activities to Hepatitis B virus Fitoterapia 2012 83 2 303 309 10.1016/j.fitote.2011.11.008 2-s2.0-84855996062 22119765 20 Huang S. X. Mou J. F. Luo Q. Mo Q. H. Zhou X. L. Anti-hepatitis B virus activity of esculetin from Microsorium fortunei in vitro and in vivo Molecules 2019 24 19 p. 3475 10.3390/molecules24193475 2-s2.0-85072637215 21 Chen H. Li J. Wu Q. Anti-HBV activities of Streblus asper and constituents of its roots Fitoterapia 2012 83 4 643 649 10.1016/j.fitote.2012.01.009 2-s2.0-84862823403 22305944 22 Li J. Meng A. P. Guan X. L. Li J. Anti-hepatitis B virus lignans from the root of Streblus asper Bioorganic & Medicinal Chemistry Letters 2013 23 7 2238 2244 10.1016/j.bmcl.2013.01.046 2-s2.0-84875212617 23434030 23 Li J. Huang Y. Guan X. L. Li J. Anti-hepatitis B virus constituents from the stem bark of Streblus asper Phytochemistry 2012 82 100 109 10.1016/j.phytochem.2012.06.023 2-s2.0-84865223639 22818524 24 Su W. Zhao J. P. Yang M. Yan H. W. Pang T. A coumarin lignanoid from the stems of Kadsura heteroclita Bioorganic & Medicinal Chemistry Letters 2015 25 7 1506 1508 10.1016/j.bmcl.2015.02.022 2-s2.0-84925506391 25736995 25 Liu S. Wei W. X. Shi K. Cao X. Zhou M. In vitro and in vivo anti-hepatitis B virus activities of the lignan niranthin isolated from Phyllanthus niruri L. Journal of Ethnopharmacology 2014 155 2 1061 1067 10.1016/j.jep.2014.05.064 2-s2.0-84906937632 25009077 26 He K. Geng C. A. Cao T. W. Wang H. L. Ma Y. B. Two new secoiridoids and other anti-hepatitis B virus active constituents from Swertia patens Journal of Asian Natural Products Research 2016 18 6 528 534 26727588 27 Zhou N. J. Geng C. A. Huang X. Y. Ma Y. B. Anti-hepatitis B virus active constituents from Swertia chirayita Fitoterapia 2015 100 27 34 10.1016/j.fitote.2014.11.011 2-s2.0-84911931677 25447162 28 Yi W. S. Research progress of flavonoids biological activity Guangzhou Chemical Industry 2012 40 2 47 50 29 Wang H. L. Geng C. A. Ma Y. B. Zhang X. M. Three new secoiridoids, swermacrolactones A-C and anti-hepatitis B virus activity from Swertia macrosperma Fitoterapia 2013 89 183 187 10.1016/j.fitote.2013.06.002 2-s2.0-84885145672 23756190 30 Cao T. W. Geng C. A. Jiang F. Q. Chemical constituents of Swertia yunnanensis and their anti-hepatitis B virus activity Fitoterapia 2013 89 175 182 10.1016/j.fitote.2013.05.023 2-s2.0-84885094538 23747320 31 Huang T. J. Tsai Y. C. Chiang S. Y. Wang G. J. Anti-viral effect of a compound isolated from Liriope platyphylla against hepatitis B virus in vitro Virus Research 2014 192 16 24 10.1016/j.virusres.2014.07.015 2-s2.0-84908128623 25150190 32 Parvez M. K. Tabish M. R. Alam P. Al-Dosari M. S. Plant-derived antiviral drugs as novel hepatitis B virus inhibitors: cell culture and molecular docking study Saudi Pharmaceutical Journal 2019 27 3 389 400 10.1016/j.jsps.2018.12.008 2-s2.0-85059469879 30976183 33 Mathayan M. Jayaraman S. Kulanthaivel L. Suresh A. Inhibition studies of HBV DNA polymerase using seed extracts of Pongamia pinnata Bioinformation 2019 15 7 506 512 10.6026/97320630015506 31485136 34 Cao T. W. Geng C. A. Ma Y. B. Zhang X. M. Zhou J. Chemical constituents of Swertia mussotii and their anti-hepatitis B virus activity Fitoterapia 2015 102 15 22 10.1016/j.fitote.2015.01.020 2-s2.0-84923019020 25665940 35 Xiao D. Y. Experimental Research of Epimedium Hyde II Anti-HBV In Vivo and In Vitro[D] 2018 Zunyi Medical University 36 Cao T. W. Geng C. A. Ma Y. B. He K. Wang H. L. Xanthones with anti-hepatitis B virus activity from Swertia mussotii Planta Medica 2013 79 8 679 700 37 Qin S. D. Wang Y. Wang W. Zhu W. M. Anti-H1N1-virus secondary metabolites from mangrove-derived aciduric fungus Penicillium sp. OUCMDZ-4736 Chinese Journal of Marine Drugs 2016 35 21 28 38 CAO T. W. GENG C. A. MA Y. B. HE K. Chemical constituents of Swertia delavayi and their anti-hepatitis B virus activity China Journal of Chinese Materia Medica 2015 40 5 897 902 26087553 39 Bu Z. L. Yu C. M. Lin W. Y. Hong P. Z. Li Y. Research progress on the synthesis of anthraquinones Chinese Journal of Synthetic Chemistry 2019 9 747 762 40 Peng Z. Fang G. Peng F. H. Pan Z. Y. Su Z. Y. Effects of Rubiadin isolated from Prismatomeris connata on anti-hepatitis B virus activity in vitro Phytotherapy Research 2017 31 12 1962 1970 10.1002/ptr.5945 2-s2.0-85031489439 29044868 41 Parvez M. K. Al-Dosari M. S. Alam P. Rehman M. T. Alajmi M. F. The anti-hepatitis B virus therapeutic potential of anthraquinones derived from Aloe vera Phytotherapy Research 2019 33 11 2960 2970 10.1002/ptr.6471 2-s2.0-85070767328 31410907 42 Lan T. Y. Research on Anti-HBV Effect and Mechanism of Hypericin 2016 KunMing University of Science and Technology 43 Zhang J. H. Liu W. T. Luo H. M. Advances in activities of terpenoids in medicinal plants Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology 2018 3 419 430 44 Huang Q. F. Huang R. B. Wei L. Chen Y. X. Antiviral activity of methyl helicterate isolated from Helicteres angustifolia (Sterculiaceae) against hepatitis B virus Antiviral Research 2013 100 2 373 381 10.1016/j.antiviral.2013.09.007 2-s2.0-84885361907 24055834 45 Zhou W. B. Zeng G. Z. Xu H. M. He W. J. Tan N. H. Astataricusones A-D and astataricusol A, five new anti-HBV shionane-type triterpenes from Aster tataricus l. f Molecules 2013 18 12 14585 14596 10.3390/molecules181214585 2-s2.0-84890892464 24287992 46 Zhou W.-B. Zeng G.-Z. Xu H.-M. He W.-J. Zhang Y.-M. Tan N.-H. Astershionones A-F, six new anti-HBV shionane-type triterpenes from Aster tataricus Fitoterapia 2014 93 98 104 10.1016/j.fitote.2013.12.021 2-s2.0-84893111564 24393620 47 Bi M. Tang C. Yu H. Monoterpenes from paeonia sinjian gensis inhibit the replication of hepatitis B virus Records of Natural Products 2013 7 4 346 350 48 Jiang Z. Y. Huang C. G. Xiong H. B. Tian K. Perovskatone A: a novel C23 terpenoid from Perovskia atriplicifolia Tetrahedron Letters 2013 54 29 3886 3888 10.1016/j.tetlet.2013.05.056 2-s2.0-84879014017 49 Gu Q. Chen Y. Cui H. Chrysanolide A, an unprecedented sesquiterpenoid trimer from the flowers of Chrysanthemum indicum L RSC Advances 2013 3 26 10168 10172 10.1039/c3ra23172k 2-s2.0-84881437886 50 Hayes P. Y. Chow S. Somerville M. J. Voss J. J. D. Fletcher M. T. Pimelotides A and B, diterpenoid ketal-lactone orthoesters with an unprecedented skeleton from Pimelea elongate Journal of Natural Products 2009 72 12 51 Zhang Z. Q. Li S. F. Zhang L. W. Chao J. B. Chemical constituents from flowers of Wikstroemia chamaedaphne and their anti-hepatitis B virus activity Chinese Traditional and Herbal Drugs 2017 48 7 52 Fang J. B. Liu Y. W. Zhang Y. W. Teng J. Duan H. Q. Antivirus constituents from Alternanthera philoxeroides Chinese Traditional and Herbal Drugs 2007 38 7 53 Jie X.-X. Geng C.-A. Huang X.-Y. Five new secoiridoid glycosides and one unusual lactonic enol ketone with anti-HBV activity from Swertia cincta Fitoterapia 2015 102 96 101 10.1016/j.fitote.2015.02.009 2-s2.0-84923888425 25721422 54 Geng C. A. Huang X. Y. Ma Y. B. Zhang X. M. Chen J. J. Synthesis of erythrocentaurin derivatives as a new class of hepatitis B virus inhibitors Bioorganic & Medicinal Chemistry Letters 2015 25 7 1568 1571 10.1016/j.bmcl.2015.02.009 2-s2.0-84925536403 25737009 55 Huang Q. F. Zhang S. J. Huang R. B. Ling W. Chen Y. X. Isolation and identification of an anti-hepatitis B virus compound from Hydrocotyle sibthorpioides Lam Journal of Ethnopharmacology 2013 150 2 568 575 10.1016/j.jep.2013.09.009 2-s2.0-84887463491 24051027 56 Liu C. Wang Y. Wu C. Dioscin's antiviral effect in vitro Virus Research 2013 172 1-2 9 14 10.1016/j.virusres.2012.12.001 2-s2.0-84873749830 23238077 57 Zhao Y. Geng C. A. Sun C. L. Ma Y. B. Huang X. Y. Cao T. W. Polyacetylenes and anti-hepatitis B virus active constituents from Artemisia capillaris Fitoterapia 2014 95 187 193 10.1016/j.fitote.2014.03.017 2-s2.0-84898900937 24685503 58 Xu Z. Wu D. L. Zhang W. Ma F. A. Advances in studies on alkaloids compounds Guangdong Chemical Industry 2014 17 84 85 59 Jiang Z.-Y. Liu W.-F. Zhang X.-M. Luo J. Ma Y.-B. Chen J.-J. Anti-HBV active constituents from Piper longum Bioorganic & Medicinal Chemistry Letters 2013 23 7 2123 2127 10.1016/j.bmcl.2013.01.118 2-s2.0-84875217995 23434420 60 Jiang Z. Y. Liu W. F. Huang C. G. Huang X. Z. New amide alkaloids from Piper longum Fitoterapia 2013 84 3 222 226 10.1016/j.fitote.2012.12.001 2-s2.0-84873354664 23232323 61 Zeng F. L. Xiang Y. F. Liang Z. R. Wang X. Huang D. E. Zhu S. N. Anti-hepatitis B virus effects of dehydrocheilanthifoline from Corydalis saxicola Journal of Chinese Medicine 2013 41 1 119 130 62 Liu Y. P. Qiu X. Y. Liu Y. Ma G. Research progress on pharmacological effect of Artemisiae Scopariae Herba Chinese Traditional and Herbal Drugs 2019 9 2235 2241 63 Geng C. A. Yang T. H. Huang X. Y. Yang J. I. Ma Y. B. Li T. Z. Anti-hepatitis B virus effects of the traditional Chinese herb Artemisia capillaris and its active enynes Journal of Ethnopharmacology 2018 10 283 289 64 Geng C.-A. Huang X.-Y. Chen X.-L. Three new anti-HBV active constituents from the traditional Chinese herb of Yin-Chen (Artemisia scoparia ) Journal of Ethnopharmacology 2015 176 12 109 117 10.1016/j.jep.2015.10.032 2-s2.0-84946125538 26505294 65 Zhou X. L. Wen Q. W. Lin X. Zhang S. J. Li Y. X. A new phenylethanoid glycoside with antioxidant and anti-HBV activity Archives of Pharmacal Research 2014 37 5 600 605 23893479 66 Huang T. J. Liu S. H. Kuo Y. C. Chen C. W. Chou S. H. The Antiviral activity of chemical compound isolated from Artemisia morrisonensis against hepatitis B virus in vitro Antiviral Research 2014 10 1 97 104 67 Zhao Y. Geng C.-A. Chen H. Isolation, synthesis and anti-hepatitis B virus evaluation of _p_ -hydroxyacetophenone derivatives from Artemisia capillaris Bioorganic & Medicinal Chemistry Letters 2015 25 7 1509 1514 10.1016/j.bmcl.2015.02.024 2-s2.0-84925511377 25737008 68 Yang X. X. Cao P. X. Huang Z. M. Liang G. Y. Synthesis and anti-hepatitis B virus activities of Matijin-Su derivatives Central South Pharmacy 2014 12 2 97 102 69 Yang L. Shi L.-p. Chen H.-j. Isothiafludine, a novel non-nucleoside compound, inhibits hepatitis B virus replication through blocking pregenomic RNA encapsidation Acta Pharmacologica Sinica 2014 35 3 410 418 10.1038/aps.2013.175 2-s2.0-84895556462 24487969 70 Xu B. X. Huang Z. M. Liu C. X. Cai Z. G. Synthesis and anti-hepatitis B virus activities of Matijing-Su derivatives Bioorganic & Medicinal Chemistry 2009 17 8 3118 3125 10.1016/j.bmc.2009.03.003 2-s2.0-64349097834 19307124 71 Kuang A. X. Lu W. Zeng X. P. Liang G. Y. Xu B. X. Synthesis and anti-HBV activity evaluation of Matijin-Su derivatives containing veratric acid Chinese Journal of New Drugs 2019 28 12 72 Kuang A. X. Zeng X. P. Cao P. Liang G. Y. Xu B. X. Synthesis and anti-HBV activity evaluation of fluorine or chlorine-substituted derivatives of Matijin-Su Journal of Guizhou Medical University 2019 4 4 418 422 73 Cui J. Lu W. Qiu J. Y. Zeng X. P. Liang G. Y. Xu B. X. Synthesis and anti-HBV activity evaluation of Matijin-Su derivatives containing trifluoromethyl Chinese Pharmaceutical Journal 2019 54 13 74 Jang X. Y. Zeng X. P. Wei K. X. Liang G. Y. Xu B. X. Synthesis and anti-HBV activities of novel N-methylated derivatives of MTS Chinese Journal of Synthetic Chemistry 2019 27 4 244 252 75 Zhou C. Xu G. C. Hu Z. X. Zeng X. P. Liu Q. C. Yuan J. Synthesis and anti-HBV activities of MTS derivatives of novel triantennary cluster galactoside Chinese Journal of Synthetic Chemistry 2018 26 3 160 167 76 Meng X. X. Wu S. Z. Yang L. Cui C. Cen Z. J. Screening of marine natural active small molecules against hepatitis B virus Modern Preventive Medicine 2018 45 23 4335 4340 77 Wang H. N. Yin Z. F. Yin X. Li H. B. Zhao G. Q. Chemical constituents from Pogonatherum crinitum and their anti-HBV activities in vitro Chinese Traditional Patent Medicine 2019 41 6 78 Wang H.-L. Cao T.-W. Jiang F.-Q. Swerpunilactones A and B, the first example of xanthone and secoiridoid heterodimers from Swertia punicea , S. hispidicalyx , and S. yunnanensis Tetrahedron Letters 2013 54 21 2710 2712 10.1016/j.tetlet.2013.03.057 2-s2.0-84876411264 79 Liu J. F. Wang Y. F. Bi Y. P. Li H. J. Jia L. Unusual nor-sesquiterpene lactone from the fruits of Illicium henryi Tetrahedron Letters 2013 54 36 4834 4836 10.1016/j.tetlet.2013.06.081 2-s2.0-84881177405 80 Huang T. J. Chou B. H. Lin C. W. Weng J. H. Synthesis and antiviral effects of isosteviol-derived analogues against the hepatitis B virus Phytochemistry 2014 99 1 107 114 10.1016/j.phytochem.2013.12.014 2-s2.0-84894239751 24461778 81 Huang T.-J. Yang C.-L. Kuo Y.-C. Synthesis and anti-hepatitis B virus activity of C4 amide-substituted isosteviol derivatives Bioorganic & Medicinal Chemistry 2015 23 4 720 728 10.1016/j.bmc.2014.12.064 2-s2.0-84964221932 25600408 82 Zhang H.-L. Dai L.-H. Wu Y.-H. Evaluation of hepatocyteprotective and anti-hepatitis B virus properties of Cichoric acid from Cichorium intybus leaves in cell culture Biological & Pharmaceutical Bulletin 2014 37 7 1214 1220 10.1248/bpb.b14-00137 2-s2.0-84904684717 24759764 83 Tsukamoto Y. Ikeda S. Uwai K. Taguchi R. Chayama K. Sakaguchi T. Rosmarinic acid is a novel inhibitor for hepatitis B virus replication targeting viral epsilon RNA-polymerase interaction PLoS One 2018 13 5, article e0197664 84 Yang Q. Li J. M. Wan H. Q. Ge L. L. Zeng X. B. Peng S. S. Anti-HBV activities of extracts and 3-caffeolquinic acid from Lonicera japonica Flower BudsJ Wuhan University Journal of Natural Sciences 2019 65 4 352 356 85 Zhao Y. Geng C.-A. Ma Y.-B. UFLC/MS-IT-TOF guided isolation of anti-HBV active chlorogenic acid analogues from Artemisia capillaris as a traditional Chinese herb for the treatment of hepatitis Journal of Ethnopharmacology 2014 156 147 154 10.1016/j.jep.2014.08.043 2-s2.0-84908455492 25219603 86 Zhu X. T. Research progress on the bioactivity of plant polysaccharide Journal of Anhui Agricultural Sciences 2008 28 12076 12077 87 Chen S. Y. Liu W. J. Cao Q. N. Ao C. J. Research advancement in bioactivity of polysaccharides from plants Feed Industry 2016 22 60 64 88 Qin X. B. Advances in the research of natural polysaccharides against hepatitis B virus World Latest Medicine Information 2017 17 20 89 Feng L. Z. Advances in extraction technology of Lentinan edodes Guangdong Chemical 2015 42 13 138 139 90 Zhang G. Q. Gai M. R. Yang J. Z. The recent efficacy observation of 62 cases of chronic B viral hepatitis was treated by lamivudine The New Medicine 2003 34 4 239 240 91 Zhao Y.-M. Yang J.-m. Liu Y.-h. Zhao M. Wang J. Ultrasound assisted extraction of polysaccharides from Lentinus edodes and its anti-hepatitis B activity in vitro International Journal of Biological Macromolecules 2018 107 Part B 2217 2223 10.1016/j.ijbiomac.2017.10.100 2-s2.0-85031751395 29051096 92 Meng M. Y. Huang R. B. Liang H. The inhibitory effects of polysaccharides from Hedyotis caudatifolia on hepatitis B virus Pharmacology and Clinics of Chinese Materia Medica 2019 35 4 38 43 93 Zhan X. D. Wang K. X. Li C. P. Study on the antihepatitis B virus effect of snail polysaccharide in vitro Chinese Journal of Experimental Traditional Medical Formulae 2008 14 3 66 68 94 Liu L. F. 128 cases of chronic hepatitis B treated with polyporus polysaccharide and hepatitis B vaccine Journal of Clinical Medicine 2009 19 6 15 16 95 Li S. F. Wang X. Gui X. E. Effects of angelica polysaccharide on the functional status of dendritic cells HBC trans-genic mice Journal of Practical Diagnosis and Therapy 2005 19 5 313 317 96 Liu X. Y. Li C. P. Wang K. X. Experimental study on polysaccharide of Cipangopaludina chinensis against HBV in vitro China Journal of Chinese Materia Medica 2013 38 6 879 883 23717972 97 Xia Q. F. Tan H. L. Experimental study on the anti - hepatitis b virus effect of polysaccharides from paniculate Shandong Medical Journal 2010 50 7 44 45 98 Zhang X. L. Yang Y. D. Song C. B. Hu Z. H. Xu Y. P. Synergy effect of oxymatrine on antiviral treatment of chronic hepatitis B Chinese Journal of Nosocomiology 2019 29 17 2635 2638