{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T09:22:32Z","timestamp":1789204952155,"version":"build-2803163510"},"reference-count":28,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T00:00:00Z","timestamp":1700006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T00:00:00Z","timestamp":1700006400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["U19 AI142759\/AI\/NIAID NIH HHS\/United States"],"award-info":[{"award-number":["U19 AI142759\/AI\/NIAID NIH HHS\/United States"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2023,11,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The unprecedented scale of the COVID-19 pandemic and the rapid evolution of SARS-CoV-2 variants underscore the need for broadly active inhibitors with a high barrier to resistance. The coronavirus main protease (M\n            <jats:sup>pro<\/jats:sup>\n            ) is an essential cysteine protease required for viral polyprotein processing and is highly conserved across human coronaviruses. Pomotrelvir is a novel M\n            <jats:sup>pro<\/jats:sup>\n            inhibitor that has recently completed a phase 2 clinical trial. In this report, we demonstrated that pomotrelvir is a potent competitive inhibitor of SARS-CoV-2 M\n            <jats:sup>pro<\/jats:sup>\n            with high selectivity against human proteases. In the enzyme assay, pomotrelvir is also active against M\n            <jats:sup>pro<\/jats:sup>\n            proteins derived from human coronaviruses CoV-229E, CoV-OC43, CoV-HKU1, CoV-NL63, MERS, and SARS-CoV. In cell-based SARS-CoV-2 replicon and SARS-CoV-2 infection assays, pomotrelvir has shown potent inhibitory activity and is broadly active against SARS-CoV-2 clinical isolates including Omicron variants. Many resistance substitutions of the M\n            <jats:sup>pro<\/jats:sup>\n            inhibitor nirmatrelvir confer cross-resistance to pomotrelvir, consistent with the finding from our enzymatic analysis that pomotrelvir and nirmatrelvir compete for the same binding site. In a SARS-CoV-2 infection assay, pomotrelvir is additive when combined with remdesivir or molnupiravir, two nucleoside analogs targeting viral RNA synthesis. In conclusion, our results from the\n            <jats:italic>in vitro<\/jats:italic>\n            characterization of pomotrelvir antiviral activity support its further clinical development as an alternative COVID-19 therapeutic option.\n          <\/jats:p>\n          <jats:p\/>","DOI":"10.1128\/aac.00840-23","type":"journal-article","created":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T13:03:41Z","timestamp":1696597421000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":32,"title":["Evaluation of\n            <i>in vitro<\/i>\n            antiviral activity of SARS-CoV-2 M\n            <sup>pro<\/sup>\n            inhibitor pomotrelvir and cross-resistance to nirmatrelvir resistance substitutions"],"prefix":"10.1128","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4559-1632","authenticated-orcid":false,"given":"Xiao","family":"Tong","sequence":"first","affiliation":[{"name":"Pardes Biosciences, Inc. , Carlsbad, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Keung","sequence":"additional","affiliation":[{"name":"Pardes Biosciences, Inc. , Carlsbad, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee D.","family":"Arnold","sequence":"additional","affiliation":[{"name":"Pardes Biosciences, Inc. , Carlsbad, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J.","family":"Stevens","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center , Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea J.","family":"Pruijssers","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center , Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seunghyi","family":"Kook","sequence":"additional","affiliation":[{"name":"Vanderbilt 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-020-00468-6"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-0190-2"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tmaid.2020.101830"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30120-1"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2020.106054"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008536"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-020-02598-6"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.0757"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b01828"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2223-y"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115491"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00672-y"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl4784"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-022-00640-y"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02815-22"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05514-2"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.add7197"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18233-x"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cll.2019.04.002"},{"key":"e_1_3_2_23_2","volume-title":"29th 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