{"doi":"10.1101/2022.03.01.482536","title":"Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening","abstract":"ABSTRACT The emergence of several zoonotic viruses in the last twenty years, especially the pandemic outbreak of SARS-CoV-2, has exposed a dearth of antiviral drug therapies for viruses with pandemic potential. Developing a diverse drug portfolio will be critical for our ability to rapidly respond to novel coronaviruses (CoVs) and other viruses with pandemic potential. Here we focus on the SARS-CoV-2 conserved macrodomain (Mac1), a small domain of non-structural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that cleaves mono-ADP-ribose (MAR) from target proteins, protects the virus from the anti-viral effects of host ADP-ribosyltransferases, and is critical for the replication and pathogenesis of CoVs. In this study, a luminescent-based high-throughput assay was used to screen ∼38,000 small molecules for those that could inhibit Mac1-ADP-ribose binding. We identified 5 compounds amongst 3 chemotypes that inhibit SARS-CoV-2 Mac1-ADP-ribose binding in multiple assays with IC 50 values less than 100 µ M, inhibit ADP-ribosylhydrolase activity, and have evidence of direct Mac1 binding. These chemotypes are strong candidates for further derivatization into highly effective Mac1 inhibitors.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":302819,"datarank":0.12019961129370428,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.01622753420971247,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.01622753420971247,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":263067,"name":"Yousef M. Alhammad","orcid":"0000-0001-8435-9042","position":1,"is_corresponding":false},{"id":263070,"name":"Peter R. McDonald","orcid":"0000-0002-1880-7414","position":2,"is_corresponding":false},{"id":263071,"name":"David K. Johnson","orcid":"0000-0003-4262-8173","position":3,"is_corresponding":false},{"id":873604,"name":"Junlin Zhuo","orcid":"0000-0002-5311-6707","position":4,"is_corresponding":false},{"id":873605,"name":"Sarah Wazir","orcid":"0000-0003-0133-2923","position":5,"is_corresponding":false},{"id":416689,"name":"Dana Ferraris","orcid":"0000-0001-5791-5939","position":6,"is_corresponding":false},{"id":618539,"name":"L. Lehtiö","orcid":"0000-0001-7250-832X","position":7,"is_corresponding":false},{"id":236295,"name":"Anthony K. L. Leung","orcid":"0000-0001-5569-4036","position":8,"is_corresponding":false},{"id":109648,"name":"Anthony R. Fehr","orcid":"0000-0003-1560-1573","position":9,"is_corresponding":false},{"id":874351,"name":"Anu Roy","orcid":null,"position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:32:20.348385Z","pmid":"35262075","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":[]}