{"doi":"10.1126/science.adm9724","title":"Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model","abstract":"The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PL pro ) is a promising but challenging drug target. We designed and synthesized 85 noncovalent PL pro inhibitors that bind to a recently discovered ubiquitin binding site and the known BL2 groove pocket near the S4 subsite. Leads inhibited PL pro with the inhibitory constant K i values from 13.2 to 88.2 nanomolar. The co-crystal structures of PL pro with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC 50 from 0.44 to 2.02 micromolar. Oral treatment with Jun12682 improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting that PL pro inhibitors are promising oral SARS-CoV-2 antiviral candidates.","journal":"Science","year":2024,"id":416607,"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":115,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9569,"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":1201089,"name":"Xiaoming Zhang","orcid":"0009-0000-8707-5715","position":1,"is_corresponding":false},{"id":1166369,"name":"Ahmadullah Ansari","orcid":"0000-0003-3398-175X","position":2,"is_corresponding":false},{"id":1054808,"name":"Prakash D. Jadhav","orcid":"0000-0001-8647-0318","position":3,"is_corresponding":false},{"id":642332,"name":"Haozhou Tan","orcid":"0000-0002-6640-8354","position":4,"is_corresponding":false},{"id":618410,"name":"Kan Li","orcid":"0000-0002-0825-1934","position":5,"is_corresponding":false},{"id":997504,"name":"Ashima Chopra","orcid":"0000-0001-7867-1507","position":6,"is_corresponding":false},{"id":1166757,"name":"Alexandra Ford","orcid":null,"position":7,"is_corresponding":false},{"id":1201090,"name":"Xiang Chi","orcid":"0009-0003-4853-7931","position":8,"is_corresponding":false},{"id":296185,"name":"Francesc X. Ruiz","orcid":"0000-0002-0457-0030","position":9,"is_corresponding":false},{"id":296186,"name":"Eddy Arnold","orcid":"0000-0003-2612-9622","position":10,"is_corresponding":false},{"id":233693,"name":"Xufang Deng","orcid":"0000-0002-7604-3627","position":11,"is_corresponding":false},{"id":107696,"name":"Jun Wang","orcid":"0000-0002-4845-4621","position":12,"is_corresponding":false},{"id":1054807,"name":"Bin Tan","orcid":"0000-0001-6295-6962","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T01:56:44.873714Z","pmid":"38547259","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":[]}