{"doi":"10.1101/2024.08.08.606661","title":"The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  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\n                  <jats:italic>in vivo</jats:italic>\n                  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\n                  <jats:italic>in vivo</jats:italic>\n                  model of SARS-CoV-2 infection. Standard 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. However, a stronger antiviral effect for AVI-4206 is observed in human airway organoids and peripheral blood monocyte-derived macrophages. 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.\n                </jats:p>","journal":null,"year":null,"id":662620,"datarank":0.38474240361923057,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.0,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":490823,"name":"Priyadarshini Jaishankar","orcid":"0009-0005-2013-8941","position":1,"is_corresponding":false},{"id":552145,"name":"G.J. Correy","orcid":"0000-0001-5155-7325","position":2,"is_corresponding":false},{"id":984322,"name":"Moira Rachman","orcid":"0000-0003-3671-8885","position":3,"is_corresponding":false},{"id":842015,"name":"Patrick C. O’Leary","orcid":"0000-0002-2919-5943","position":4,"is_corresponding":false},{"id":385627,"name":"Taha Y. Taha","orcid":"0000-0002-7344-7490","position":5,"is_corresponding":false},{"id":374969,"name":"Yusuke Matsui","orcid":"0000-0002-6016-2867","position":6,"is_corresponding":false},{"id":901043,"name":"Francisco J. Zapatero‐Belinchón","orcid":"0000-0002-2751-8411","position":7,"is_corresponding":false},{"id":931762,"name":"Maria McCavitt-Malvido","orcid":"0009-0006-4731-6047","position":8,"is_corresponding":false},{"id":890303,"name":"Yagmur U. Doruk","orcid":"0000-0002-3388-7803","position":9,"is_corresponding":false},{"id":1326745,"name":"Maisie GV Stevens","orcid":"0009-0004-9732-0349","position":10,"is_corresponding":false},{"id":842014,"name":"Morgan E. Diolaiti","orcid":"0000-0001-5900-3060","position":11,"is_corresponding":false},{"id":739776,"name":"Manasi P. Jogalekar","orcid":"0000-0003-1307-4829","position":12,"is_corresponding":false},{"id":540844,"name":"Huadong Chen","orcid":"0000-0003-4681-0853","position":13,"is_corresponding":false},{"id":1472,"name":"Alicia Richards","orcid":"0000-0002-4869-2945","position":14,"is_corresponding":false},{"id":1442388,"name":"Pornparn Kongpracha","orcid":"0000-0003-1759-213X","position":15,"is_corresponding":false},{"id":689401,"name":"Sofia Bali","orcid":"0000-0002-4046-7081","position":16,"is_corresponding":false},{"id":28877,"name":"Mauricio Montaño","orcid":"0000-0002-0353-0037","position":17,"is_corresponding":false},{"id":1333387,"name":"Julia Rosecrans","orcid":"0009-0000-3111-5933","position":18,"is_corresponding":false},{"id":231443,"name":"Michael A. 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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\n                  <jats:italic>in vivo</jats:italic>\n                  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\n                  <jats:italic>in vivo</jats:italic>\n                  model of SARS-CoV-2 infection. Standard 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. However, a stronger antiviral effect for AVI-4206 is observed in human airway organoids and peripheral blood monocyte-derived macrophages. 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.\n                </jats:p>","is_dataset_classified":null,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39149230","pmcid":null,"openalex_id":"https://openalex.org/W4401487541","authors":[],"funders":[{"funder_name":"NIAID NIH HHS","grant_id":"U19AI171110","title":null},{"funder_name":"","grant_id":"NIH Division of Intramural Research","title":null},{"funder_name":"National Institutes of Health","grant_id":"3P30GM133894-06S1","title":"A Synchrotron Radiation Structural Biology Resource"},{"funder_name":"National Institutes of Health","grant_id":"1U19AI171110-01","title":"QCRG Pandemic Response Program"},{"funder_name":"National Institutes of Health","grant_id":"2P30GM124169-06","title":"ALS Efficiently Networking Advanced Beam Line Experiments (ALS-ENABLE)"},{"funder_name":"NIGMS NIH HHS","grant_id":"P30 GM124169","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"P30 GM133894","title":null}],"total_grants":7,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2024,"count":3},{"year":2025,"count":8},{"year":2026,"count":1}],"oa_status":"green","license":"cc-by","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2024/08/09/2024.08.08.606661.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2024/08/09/2024.08.08.606661.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2024.08.08.606661","host_type":"publisher"},{"url":"https://doi.org/10.1101/2024.08.08.606661","host_type":"repository"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39149230","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11326214/","host_type":"repository"},{"url":"https://doi.org/10.7554/elife.103484.2","host_type":""},{"url":"https://doi.org/10.7554/elife.103484.3","host_type":""},{"url":"https://doi.org/10.7554/elife.103484","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/41258893","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/39149230/","host_type":""},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12629595/","host_type":""},{"url":"https://doi.org/10.7554/eLife.103484","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/41258893/","host_type":""}],"fields_of_study":["PARP inhibition in cancer therapy","Calcium signaling and nucleotide metabolism","Plant Virus Research Studies","0301 basic medicine","03 medical and health sciences"],"mesh_terms":[],"keywords":["Viral replication","Innate immune system","Immune system","Biology","Virology","Mechanism (biology)","Viral life cycle","Virus","Computational biology","Immunology","Microbiology and Infectious Disease","SARS-CoV-2","Macrophages","COVID-19","Virus Replication","Antiviral Agents","Article","Immunity, Innate","COVID-19 Drug Treatment","Mice","Disease Models, Animal","Humans","Animals","N-Glycosyl Hydrolases"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Responsible consumption and production"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-12T16:28:08.344219Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}