{"doi":"10.1021/acsinfecdis.3c00565","title":"Design, Synthesis, X-ray Crystallography, and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease","abstract":"Highly contagious SARS-CoV-2 coronavirus has infected billions of people worldwide with flu-like symptoms since its emergence in 2019. It has caused deaths of several million people. The viral main protease (Mpro) is essential for SARS-CoV-2 replication and therefore a drug target. Several series of covalent inhibitors of Mpro were designed and synthesized. Structure–activity relationship studies show that (1) several chloroacetamide- and epoxide-based compounds targeting Cys145 are potent inhibitors with IC 50 values as low as 0.49 μM and (2) Cys44 of Mpro is not nucleophilic for covalent inhibitor design. High-resolution X-ray studies revealed the protein–inhibitor interactions and mechanisms of inhibition. It is of interest that Cys145 preferably attacks the more hindered C α atom of several epoxide inhibitors. Chloroacetamide inhibitor 13 and epoxide inhibitor 30 were found to inhibit cellular SARS-CoV-2 replication with an EC 68 (half-log reduction of virus titer) of 3 and 5 μM. These compounds represent new pharmacological leads for anti-SARS-CoV-2 drug development.","journal":"ACS Infectious Diseases","year":2024,"id":434612,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9563,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":401775,"name":"Teck Khiang Chua","orcid":"0000-0001-6569-0813","position":1,"is_corresponding":false},{"id":672146,"name":"Xin Li","orcid":"0000-0002-0189-4371","position":2,"is_corresponding":false},{"id":39688,"name":"Yuan Yao","orcid":"0000-0002-4543-2988","position":3,"is_corresponding":false},{"id":1241401,"name":"Balakrishna Moku","orcid":"0000-0002-3984-8514","position":4,"is_corresponding":false},{"id":1241402,"name":"Chandra Bhushan Mishra","orcid":"0000-0001-9274-5912","position":5,"is_corresponding":false},{"id":236974,"name":"Vasanthi Avadhanula","orcid":"0000-0003-4016-7588","position":6,"is_corresponding":false},{"id":236976,"name":"Pedro A. Piedra","orcid":"0000-0002-5839-0879","position":7,"is_corresponding":false},{"id":331039,"name":"Yongcheng Song","orcid":"0000-0003-2611-2476","position":8,"is_corresponding":false},{"id":393305,"name":"Md Ashraf-Uz-Zaman","orcid":"0000-0003-1327-3166","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-19T01:59:58.582186Z","pmid":"38192109","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":[]}