
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

39149230
10.1101/2024.08.08.606661
preprint
2
Article
The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2
Suryawanshi Rahul K. http://orcid.org/0000-0001-8374-669X

Jaishankar Priyadarshini http://orcid.org/0009-0005-2013-8941

Correy Galen J. http://orcid.org/0000-0001-5155-7325

Rachman Moira M. http://orcid.org/0000-0003-3671-8885

O’Leary Patrick C. http://orcid.org/0000-0002-2919-5943

Taha Taha Y. http://orcid.org/0000-0002-7344-7490

Zapatero-Belinchón Francisco J. http://orcid.org/0000-0002-2751-8411

McCavitt-Malvido Maria http://orcid.org/0009-0006-4731-6047

Doruk Yagmur U. http://orcid.org/0000-0002-3388-7803

Stevens Maisie G. V. http://orcid.org/0009-0004-9732-0349

Diolaiti Morgan E. http://orcid.org/0000-0001-5900-3060

Jogalekar Manasi P. http://orcid.org/0000-0003-1307-4829

Richards Alicia L. http://orcid.org/0000-0002-4869-2945

Montano Mauricio http://orcid.org/0000-0002-0353-0037

Rosecrans Julia http://orcid.org/0009-0000-3111-5933

Matthay Michael http://orcid.org/0000-0003-3039-8155

Togo Takaya http://orcid.org/0000-0003-0243-0760

Gonciarz Ryan L. http://orcid.org/0000-0002-6600-7032

Gopalkrishnan Saumya http://orcid.org/0009-0003-6713-4492

Neitz R. Jeffrey http://orcid.org/0000-0002-2247-9345

Krogan Nevan J. http://orcid.org/0000-0003-4902-337X

Swaney Danielle L. http://orcid.org/0000-0001-6119-6084

Shoichet Brian K. http://orcid.org/0000-0002-6098-7367

Ott Melanie http://orcid.org/0000-0002-5697-1274

Renslo Adam R. http://orcid.org/0000-0002-1240-2846

Ashworth Alan http://orcid.org/0000-0003-1446-7878

Fraser James S. http://orcid.org/0000-0002-5080-2859

29 8 2024
2024.08.08.606661https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
http://biorxiv.org/lookup/doi/10.1101/2024.08.08.606661
nihpp-2024.08.08.606661.pdf
Abstract

SARS-CoV-2 continues to pose a threat to public health. Current therapeutics remain limited to direct acting antivirals that lack distinct mechanisms of action and are already showing signs of viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) that plays an important role in the coronaviral lifecycle by suppressing host innate immune responses. Genetic inactivation of Mac1 abrogates viral replication in vivo by potentiating host innate immune responses. However, it is unknown whether this can be achieved by pharmacologic inhibition and can therefore be exploited therapeutically. Here we report a potent and selective lead small molecule, AVI-4206, that is effective in an in vivo model of SARS-CoV-2 infection. Cellular models indicate that AVI-4206 has high target engagement and can weakly inhibit viral replication in a gamma interferon- and Mac1 catalytic activity-dependent manner; a stronger antiviral effect for AVI-4206 is observed in human airway organoids. In an animal model of severe SARS-CoV-2 infection, AVI-4206 reduces viral replication, potentiates innate immune responses, and leads to a survival benefit. Our results provide pharmacological proof of concept that Mac1 is a valid therapeutic target via a novel immune-restoring mechanism that could potentially synergize with existing therapies targeting distinct, essential aspects of the coronaviral life cycle. This approach could be more widely used to target other viral macrodomains to develop antiviral therapeutics beyond COVID-19.
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pmc
