{"doi":"10.1101/2023.01.28.525917","title":"SARS-CoV-2 M <sup>pro</sup> protease variants of concern display altered viral and host target processing but retain potency towards antivirals","abstract":"ABSTRACT Main protease of SARS-CoV-2 (M pro ) is the most promising drug target against coronaviruses due to its essential role in virus replication. With newly emerging variants there is a concern that mutations in M pro may alter structural and functional properties of protease and subsequently the potency of existing and potential antivirals. We explored the effect of 31 mutations belonging to 5 variants of concern (VOC) on catalytic parameters and substrate specificity, which revealed changes in substrate binding and rate of cleavage of a viral peptide. Crystal structures of 11 M pro mutants provided structural insight into their altered functionality. Additionally, we show M pro mutations influence proteolysis of an immunomodulatory host protein Galectin-8 (Gal-8) and subsequent significant decrease in cytokine secretion, providing evidence for alterations in escape of host-antiviral mechanisms. Accordingly, mutations associated with the highly virulent Delta VOC resulted in significant increase in Gal-8 cleavage. Importantly, IC50s of nirmatrelvir (Pfizer) and our irreversible inhibitor AVI-8053 demonstrated no changes in potency for both drugs for all mutants, suggesting M pro will remain a high-priority antiviral drug candidate as SARS-CoV-2 evolves.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":398319,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9544,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":227819,"name":"Elena Arutyunova","orcid":"0000-0003-4119-3622","position":1,"is_corresponding":false},{"id":656412,"name":"Jimmy Lu","orcid":"0000-0002-4090-5176","position":2,"is_corresponding":false},{"id":227817,"name":"Muhammad Bashir Khan","orcid":"0000-0002-4164-9573","position":3,"is_corresponding":false},{"id":227429,"name":"Wioletta Rut","orcid":"0000-0003-1261-5566","position":4,"is_corresponding":false},{"id":227431,"name":"Mikołaj Żmudziński","orcid":"0000-0002-9792-9160","position":5,"is_corresponding":false},{"id":1027441,"name":"Shima Shahbaz","orcid":null,"position":6,"is_corresponding":false},{"id":662713,"name":"Jegan Iyyathurai","orcid":null,"position":7,"is_corresponding":false},{"id":1026712,"name":"Eman W. Moussa","orcid":"0009-0007-7113-9092","position":8,"is_corresponding":false},{"id":1026713,"name":"Zoe Turner","orcid":"0000-0002-3130-5208","position":9,"is_corresponding":false},{"id":656411,"name":"Bing Bai","orcid":"0000-0003-4102-305X","position":10,"is_corresponding":false},{"id":227820,"name":"Tess Lamer","orcid":"0000-0002-1511-4540","position":11,"is_corresponding":false},{"id":656414,"name":"James A. Nieman","orcid":"0000-0002-5087-0819","position":12,"is_corresponding":false},{"id":227826,"name":"John C. Vederas","orcid":"0000-0002-2996-0326","position":13,"is_corresponding":false},{"id":485307,"name":"Olivier Julien","orcid":"0000-0001-7068-7299","position":14,"is_corresponding":false},{"id":227436,"name":"Marcin Drąg","orcid":"0000-0001-8510-1967","position":15,"is_corresponding":false},{"id":1026714,"name":"Shokrollah Elahi","orcid":"0000-0002-7215-2009","position":16,"is_corresponding":false},{"id":227824,"name":"Howard S. Young","orcid":"0000-0002-5990-8422","position":17,"is_corresponding":false},{"id":229741,"name":"M. Joanne Lemieux","orcid":null,"position":18,"is_corresponding":false},{"id":1026711,"name":"Sizhu Amelia Chen","orcid":"0000-0003-2412-2697","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T01:19:43.776284Z","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":[]}