{"doi":"10.1016/j.celrep.2024.114929","title":"An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis in vivo","abstract":"Safe, effective, and low-cost oral antiviral therapies are needed to treat those at high risk for developing severe COVID-19. To that end, we performed a high-throughput screen to identify non-peptidic, non-covalent inhibitors of the SARS-CoV-2 main protease (Mpro), an essential enzyme in viral replication. NZ-804 was developed from a screening hit through iterative rounds of structure-guided medicinal chemistry. NZ-804 potently inhibits SARS-CoV-2 Mpro (0.009 μM IC 50 ) as well as SARS-CoV-2 replication in human lung cell lines (0.008 μM EC 50 ) and primary human airway epithelial cell cultures. Antiviral activity is maintained against distantly related sarbecoviruses and endemic human CoV OC43. In SARS-CoV-2 mouse and hamster disease models, NZ-804 therapy given once or twice daily significantly diminished SARS-CoV-2 replication and pathogenesis. NZ-804 synthesis is low cost and uncomplicated, simplifying global production and access. These data support the exploration of NZ-804 as a therapy for COVID-19 and future emerging sarbecovirus infections.","journal":"Cell Reports","year":2024,"id":439287,"datarank":0.39776802814293427,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.03808373722317858,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.03808373722317858,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":8,"citers_with_citation_signal":4,"citers_with_endowment":4,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"is_data_producer":true,"deposit_databanks":{"SRA":["PRJNA1061174"],"PDB":["8W1U","8W1T"]},"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":798114,"name":"Su Tang","orcid":"0000-0002-6993-1212","position":1,"is_corresponding":false},{"id":1250602,"name":"Xuelin Bian","orcid":null,"position":2,"is_corresponding":false},{"id":673292,"name":"Maloy Kumar Parai","orcid":null,"position":3,"is_corresponding":false},{"id":286214,"name":"Inna V. 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