{"doi":"10.1126/sciadv.adv8875","title":"Strategy to overcome a nirmatrelvir resistance mechanism in the SARS-CoV-2 nsp5 protease","abstract":"E166V in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nsp5 protease confers strong resistance to the antiviral component of Paxlovid, nirmatrelvir (NIR), in passaging and clinical samples. In SARS-CoV-2 replicons, E166V drastically decreased Washington (WA1) but not Omicron (BA.1) fitness (20- versus 2-fold), suggesting a lower barrier to resistance in the BA.1 strain and consistent with observed differences in respective nsp5 dimerization affinities. Crystal structures reveal a steric clash between the rigid, bulky NIR tert -butyl group and the β-branched Val 166 , disrupting the covalent binding of NIR to the catalytic Cys 145 and leading to high resistance in BA.1 and WA1 replicons. NIR-resistant replicons remained susceptible to GC376, which can still covalently bind Cys 145 by avoiding a steric clash with Val 166 through “wiggling and jiggling.” Hence, strategic flexibility is a strategy that will help design second-generation antivirals against NIR-resistant viruses.","journal":"Science Advances","year":2025,"id":516256,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"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":253446,"name":"Shuiyun Lan","orcid":"0009-0002-4101-9894","position":1,"is_corresponding":false},{"id":630216,"name":"Ryan L. Slack","orcid":"0000-0002-5928-6205","position":2,"is_corresponding":false},{"id":900031,"name":"Zachary C. Lorson","orcid":"0009-0002-1404-9086","position":3,"is_corresponding":false},{"id":748768,"name":"Andres Emanuelli Castaner","orcid":"0009-0005-1275-9684","position":4,"is_corresponding":false},{"id":388176,"name":"Rachel Lee","orcid":"0000-0003-2704-839X","position":5,"is_corresponding":false},{"id":870035,"name":"Kristin Edwards","orcid":"0000-0002-2168-8241","position":6,"is_corresponding":false},{"id":494962,"name":"Huanchun Zhang","orcid":null,"position":7,"is_corresponding":false},{"id":667510,"name":"Jasper Lee","orcid":"0000-0003-0472-827X","position":8,"is_corresponding":false},{"id":404741,"name":"William A. Cantara","orcid":"0000-0002-3214-7635","position":9,"is_corresponding":false},{"id":578317,"name":"Maria E. Cilento","orcid":"0000-0001-7597-1248","position":10,"is_corresponding":false},{"id":802784,"name":"Hongwang Zhang","orcid":"0000-0002-0032-9004","position":11,"is_corresponding":false},{"id":929758,"name":"Ramyani De","orcid":"0000-0001-5534-0705","position":12,"is_corresponding":false},{"id":314480,"name":"Franck Amblard","orcid":"0009-0002-6235-4050","position":13,"is_corresponding":false},{"id":253447,"name":"Philip R. Tedbury","orcid":"0000-0001-8151-4967","position":14,"is_corresponding":false},{"id":494263,"name":"Karen A. Kirby","orcid":"0000-0003-2468-4796","position":15,"is_corresponding":false},{"id":228075,"name":"Raymond F. Schinazi","orcid":"0000-0002-6688-3614","position":16,"is_corresponding":false},{"id":253448,"name":"Stefan G. Sarafianos","orcid":"0000-0002-5840-154X","position":17,"is_corresponding":false},{"id":1160140,"name":"Grace Neilsen","orcid":"0000-0001-9344-1160","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-19T02:48:49.486328Z","pmid":"40479048","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":[]}