{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T05:19:25Z","timestamp":1792387165531,"version":"4.4.0"},"reference-count":50,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"6690","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Science"],"published-print":{"date-parts":[[2024,3,29]]},"abstract":"<jats:p>\n                    The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PL\n                    <jats:sup>pro<\/jats:sup>\n                    ) is a promising but challenging drug target. We designed and synthesized 85 noncovalent PL\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors that bind to a recently discovered ubiquitin binding site and the known BL2 groove pocket near the S4 subsite. Leads inhibited PL\n                    <jats:sup>pro<\/jats:sup>\n                    with the inhibitory constant K\n                    <jats:sub>i<\/jats:sub>\n                    values from 13.2 to 88.2 nanomolar. The co-crystal structures of PL\n                    <jats:sup>pro<\/jats:sup>\n                    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\n                    <jats:sub>50<\/jats:sub>\n                    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\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors are promising oral SARS-CoV-2 antiviral candidates.\n                  <\/jats:p>","DOI":"10.1126\/science.adm9724","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T13:59:47Z","timestamp":1711634387000},"page":"1434-1440","update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":118,"title":["Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model"],"prefix":"10.1126","volume":"383","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6295-6962","authenticated-orcid":true,"given":"Bin","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8707-5715","authenticated-orcid":true,"given":"Xiaoming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3398-175X","authenticated-orcid":true,"given":"Ahmadullah","family":"Ansari","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA."},{"name":"Department of Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8647-0318","authenticated-orcid":true,"given":"Prakash","family":"Jadhav","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6640-8354","authenticated-orcid":true,"given":"Haozhou","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashima","family":"Chopra","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA."},{"name":"Department of Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Ford","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4853-7931","authenticated-orcid":true,"given":"Xiang","family":"Chi","sequence":"additional","affiliation":[{"name":"Department Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0457-0030","authenticated-orcid":true,"given":"Francesc Xavier","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA."},{"name":"Department of Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2612-9622","authenticated-orcid":true,"given":"Eddy","family":"Arnold","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA."},{"name":"Department of Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7604-3627","authenticated-orcid":true,"given":"Xufang","family":"Deng","sequence":"additional","affiliation":[{"name":"Department Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA."},{"name":"Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4845-4621","authenticated-orcid":true,"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00672-y"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)00519-0"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciac180"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl4784"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00117"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciac933"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40261-023-01265-8"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00632-22"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05514-2"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.3c00538"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abo0718"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29104-y"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciad494"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.24963"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.medj.2023.08.001"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abd4596"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2601-5"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38031-5"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2014.12.015"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00303"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2017.11.001"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202200440"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.1c00519"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c01307"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-37254-w"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202003732"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm501853m"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0805240105"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/tx500134g"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2020106275"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04630-3"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1010782"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202317376"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2022.04.007"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202317580"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkac257"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2021.05.008"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798316018210"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.106634"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.3390\/v13091743"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0356-z"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abe0751"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21060-3"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(97)76066-X"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4224"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444913000061"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444911007773"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0021889807021206"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444904019158"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444912001308"}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.adm9724","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T13:59:56Z","timestamp":1711634396000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.adm9724"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,29]]},"references-count":50,"journal-issue":{"issue":"6690","published-print":{"date-parts":[[2024,3,29]]}},"alternative-id":["10.1126\/science.adm9724"],"URL":"https:\/\/doi.org\/10.1126\/science.adm9724","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.12.01.569653","asserted-by":"object"}]},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,29]]},"assertion":[{"value":"2023-11-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}