{"doi":"10.1101/2024.08.19.608619","title":"Discovery of potent SARS-CoV-2 nsp3 macrodomain inhibitors uncovers lack of translation to cellular antiviral response","abstract":"A strategy for pandemic preparedness is the development of antivirals against a wide set of viral targets with complementary mechanisms of action. SARS-CoV-2 nsp3-mac1 is a viral macrodomain with ADP-ribosylhydrolase activity, which counteracts host immune response. Targeting the virus' immunomodulatory functionality offers a differentiated strategy to inhibit SARS-CoV-2 compared to approved therapeutics, which target viral replication directly. Here we report a fragment-based lead generation campaign guided by computational approaches. We discover tool compounds which inhibit nsp3-mac1 activity at low nanomolar concentrations, and with responsive structure-activity relationships, high selectivity, and drug-like properties. Using our inhibitors, we show that inhibition of nsp3-mac1 increases ADP-ribosylation, but surprisingly does not translate to demonstrable antiviral activity in cell culture and iPSC-derived pneumocyte models. Further, no synergistic activity is observed in combination with interferon gamma, a main protease inhibitor, nor a papain-like protease inhibitor. Our results question the extent to which targeting modulation of innate immunity-driven ADP-ribosylation can influence SARS-CoV-2 replication. Moreover, these findings suggest that nsp3-mac1 might not be a suitable target for antiviral therapeutics development.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":484723,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1327344,"name":"Isabelle Amick","orcid":null,"position":1,"is_corresponding":false},{"id":1326879,"name":"J.C. Aschenbrenner","orcid":"0000-0002-4318-0481","position":2,"is_corresponding":false},{"id":60987,"name":"Haim Barr","orcid":"0000-0001-9192-3983","position":3,"is_corresponding":false},{"id":773476,"name":"Jared Benjamin","orcid":"0000-0002-0328-0461","position":4,"is_corresponding":false},{"id":3208,"name":"Alexander Brandis","orcid":"0000-0001-9604-2229","position":5,"is_corresponding":false},{"id":501442,"name":"Galit Cohen","orcid":"0000-0001-6727-5023","position":6,"is_corresponding":false},{"id":631404,"name":"Randy Diaz-Tapia","orcid":null,"position":7,"is_corresponding":false},{"id":1327345,"name":"Shirly Duberstein","orcid":null,"position":8,"is_corresponding":false},{"id":1327346,"name":"Jessica Dixon","orcid":null,"position":9,"is_corresponding":false},{"id":1327347,"name":"David Cousins","orcid":null,"position":10,"is_corresponding":false},{"id":1059372,"name":"M. Fairhead","orcid":"0000-0001-5361-3933","position":11,"is_corresponding":false},{"id":552147,"name":"D. Fearon","orcid":"0000-0003-3529-7863","position":12,"is_corresponding":false},{"id":1327348,"name":"James Frick","orcid":null,"position":13,"is_corresponding":false},{"id":1327349,"name":"James Gayvert","orcid":null,"position":14,"is_corresponding":false},{"id":557429,"name":"André S. Godoy","orcid":"0000-0002-0613-9164","position":15,"is_corresponding":false},{"id":1327350,"name":"Ed J. Griffin","orcid":null,"position":16,"is_corresponding":false},{"id":273794,"name":"K. Huber","orcid":"0000-0002-1103-5300","position":17,"is_corresponding":false},{"id":1003047,"name":"L. Koekemoer","orcid":"0000-0001-9226-9127","position":18,"is_corresponding":false},{"id":1171213,"name":"Noa Lahav","orcid":null,"position":19,"is_corresponding":false},{"id":1197981,"name":"Peter Marples","orcid":"0000-0002-8787-7969","position":20,"is_corresponding":false},{"id":1478,"name":"Briana L. McGovern","orcid":"0000-0002-0492-9904","position":21,"is_corresponding":false},{"id":1031968,"name":"Tevie Mehlman","orcid":"0000-0002-2614-7583","position":22,"is_corresponding":false},{"id":1326880,"name":"Matthew C. Robinson","orcid":"0009-0001-3935-9083","position":23,"is_corresponding":false},{"id":1326881,"name":"Usha Singh","orcid":"0000-0003-4177-0848","position":24,"is_corresponding":false},{"id":1326882,"name":"Tamás Szommer","orcid":"0000-0002-3811-4068","position":25,"is_corresponding":false},{"id":1326883,"name":"Charles W.E. Tomlinson","orcid":"0000-0002-1845-6028","position":26,"is_corresponding":false},{"id":1080889,"name":"Thomas R. Vargo","orcid":"0009-0003-4203-5754","position":27,"is_corresponding":false},{"id":552166,"name":"F. von Delft","orcid":"0000-0003-0378-0017","position":28,"is_corresponding":false},{"id":1326884,"name":"Si-Yi Wang","orcid":"0000-0001-5381-7661","position":29,"is_corresponding":false},{"id":1481,"name":"Kris M. White","orcid":"0000-0003-0889-0506","position":30,"is_corresponding":false},{"id":745700,"name":"Eleanor C Williams","orcid":"0000-0002-8023-9550","position":31,"is_corresponding":false},{"id":1326885,"name":"Max Winokan","orcid":"0000-0002-1318-4422","position":32,"is_corresponding":false},{"id":686506,"name":"Alpha A. Lee","orcid":"0000-0002-9616-3108","position":0,"is_corresponding":true}],"reference_count":31,"raw_metadata":null,"created_at":"2026-07-19T02:07:42.971417Z","pmid":"39229055","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":[]}