{"doi":"10.1101/2022.04.29.490044","title":"A Novel Y-Shaped, S-O-N-O-S-Bridged Crosslink between Three Residues C22, C44, and K61 Is a Redox Switch of the SARS-CoV-2 Main Protease","abstract":"ABSTRACT As the COVID-19 pathogen, SARS-CoV-2 relies on its main protease (M Pro ) for pathogenesis and replication. During the crystallographic analyses of M Pro crystals that were exposed to the air, a uniquely Y-shaped, S-O-N-O-S-bridged posttranslational crosslink that connects three residues C22, C44, and K61 at their side chains was frequently observed. As a novel posttranslational modification, this crosslink serves as a redox switch to regulate the catalytic activity of M Pro , a demonstrated drug target of COVID-19. The formation of this linkage leads to a much more opened active site that can be potentially targeted for the development of novel SARS-CoV-2 antivirals. The inactivation of M Pro by this crosslink indicates that small molecules that lock M Pro in the crosslinked form can be potentially used with other active site-targeting molecules such as paxlovid for synergistic effects in inhibiting the SARS-CoV-2 viral replication. Therefore, this new finding reveals a unique aspect of the SARS-CoV-2 pathogenesis and is potentially paradigm-shifting in our current understanding of the function of M Pro and the development of its inhibitors as COVID-19 antivirals.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":300043,"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":0.951,"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":910681,"name":"Syuan‐Ting Kuo","orcid":null,"position":1,"is_corresponding":false},{"id":264699,"name":"Lauren R. Blankenship","orcid":"0000-0002-1714-4399","position":2,"is_corresponding":false},{"id":264700,"name":"Yan Sheng","orcid":"0000-0002-1942-9144","position":3,"is_corresponding":false},{"id":249510,"name":"Banumathi Sankaran","orcid":"0000-0002-3266-8131","position":4,"is_corresponding":false},{"id":264702,"name":"Pingwei Li","orcid":"0000-0002-1815-3107","position":5,"is_corresponding":false},{"id":63441,"name":"Carol A. Fierke","orcid":"0000-0002-1481-0579","position":6,"is_corresponding":false},{"id":323307,"name":"David H. Russell","orcid":"0000-0003-0830-3914","position":7,"is_corresponding":false},{"id":891576,"name":"Xin Yan","orcid":"0000-0002-8292-130X","position":8,"is_corresponding":false},{"id":264703,"name":"Shiqing Xu","orcid":"0000-0001-6260-9290","position":9,"is_corresponding":false},{"id":264704,"name":"Wenshe Ray Liu","orcid":"0000-0002-7078-6534","position":10,"is_corresponding":false},{"id":264693,"name":"Kai S. Yang","orcid":"0000-0002-1890-4169","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T00:31:49.412501Z","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":[]}