{"doi":"10.1101/2025.10.11.681833","title":"Discovery of AVI-6451, a Potent and Selective Inhibitor of the SARS-CoV-2 ADP-Ribosylhydrolase Mac1 with Oral Efficacy in vivo","abstract":"ABSTRACT The COVID-19 pandemic made plain the need for effective antivirals acting on novel antiviral targets, among which viral macrodomains have attracted considerable attention. We recently described AVI-4206 ( 1 ), a potent and selective inhibitor of the SARS-CoV-2 ADP-ribosylhydrolase Mac1 based on a 9 H -pyrimido[4,5- b ]indole core, the first Mac1 inhibitor to demonstrate antiviral efficacy in mouse models of SARS-CoV-2 infection, but requiring IP administration and frequent dosing. Herein we describe an extensive, structurally enabled medicinal chemistry effort to identify orally bioavailable Mac1 inhibitors by addressing permeability and efflux liabilities of 1 and many of its analogs. Multiple strategies were pursued to overcome these issues, including replacing a urea function to reduce hydrogen bond donor count. While heterocyclic urea mimetics could deliver analogs like AVI-6318 ( 3 ) with potencies and ADME profiles similar to 1 , abrogation of the P-gp liability was finally achieved with entirely non-polar substituents in place of urea. Thus, AVI-6451 ( 4 ) is a potent Mac1 inhibitor lead with low intrinsic clearance, high oral bioavailability, and antiviral efficacy with once-daily oral administration in a mouse model of SARS-CoV-2 infection.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":555786,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9443,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":552145,"name":"G.J. Correy","orcid":"0000-0001-5155-7325","position":1,"is_corresponding":false},{"id":374969,"name":"Yusuke Matsui","orcid":"0000-0002-6016-2867","position":2,"is_corresponding":false},{"id":1012419,"name":"Takaya Togo","orcid":"0000-0003-0243-0760","position":3,"is_corresponding":false},{"id":984322,"name":"Moira Rachman","orcid":"0000-0003-3671-8885","position":4,"is_corresponding":false},{"id":1326745,"name":"Maisie GV Stevens","orcid":"0009-0004-9732-0349","position":5,"is_corresponding":false},{"id":733796,"name":"Eric R. Hantz","orcid":"0000-0002-2588-7619","position":6,"is_corresponding":false},{"id":1454626,"name":"Jeffrey Zheng","orcid":"0000-0003-4225-7077","position":7,"is_corresponding":false},{"id":842014,"name":"Morgan E. Diolaiti","orcid":"0000-0001-5900-3060","position":8,"is_corresponding":false},{"id":28877,"name":"Mauricio Montaño","orcid":"0000-0002-0353-0037","position":9,"is_corresponding":false},{"id":385627,"name":"Taha Y. Taha","orcid":"0000-0002-7344-7490","position":10,"is_corresponding":false},{"id":1333387,"name":"Julia Rosecrans","orcid":"0009-0000-3111-5933","position":11,"is_corresponding":false},{"id":1455111,"name":"Julius Pampel","orcid":null,"position":12,"is_corresponding":false},{"id":1363,"name":"Nevan J. Krogan","orcid":"0000-0003-4902-337X","position":13,"is_corresponding":false},{"id":106698,"name":"Brian K. Shoichet","orcid":"0000-0002-6098-7367","position":14,"is_corresponding":false},{"id":7895,"name":"Alan Ashworth","orcid":"0000-0003-1446-7878","position":15,"is_corresponding":false},{"id":103701,"name":"Mélanie Ott","orcid":"0000-0002-5697-1274","position":16,"is_corresponding":false},{"id":63530,"name":"James S. Fraser","orcid":"0000-0002-5080-2859","position":17,"is_corresponding":false},{"id":490827,"name":"Adam R. Renslo","orcid":"0000-0002-1240-2846","position":18,"is_corresponding":false},{"id":490823,"name":"Priyadarshini Jaishankar","orcid":"0009-0005-2013-8941","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:55:03.976486Z","pmid":"41279160","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":[]}