{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T17:31:34Z","timestamp":1793727094946,"version":"4.6.1"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"17","license":[{"start":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T00:00:00Z","timestamp":1713139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM032136"],"award-info":[{"award-number":["GM032136"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R24OD026440"],"award-info":[{"award-number":["R24OD026440"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"HHS | NIH | NIAID | Division of Intramural Research","doi-asserted-by":"publisher","award":["1U19AI171443"],"award-info":[{"award-number":["1U19AI171443"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32 GM148333"],"award-info":[{"award-number":["T32 GM148333"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,4,23]]},"abstract":"<jats:p>\n                    As the SARS-CoV-2 virus continues to spread and mutate, it remains important to focus not only on preventing spread through vaccination but also on treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a SARS-CoV-2 main protease (M\n                    <jats:sup>pro<\/jats:sup>\n                    ) DAA, has been significant for treatment of patients. A limitation of this DAA, however, is that the antiviral component, nirmatrelvir, is rapidly metabolized and requires inclusion of a CYP450 3A4 metabolic inhibitor, ritonavir, to boost levels of the active drug. Serious drug\u2013drug interactions can occur with Paxlovid for patients who are also taking other medications metabolized by CYP4503A4, particularly transplant or otherwise immunocompromised patients who are most at risk for SARS-CoV-2 infection and the development of severe symptoms. Developing an alternative antiviral with improved pharmacological properties is critical for treatment of these patients. By using a computational and structure-guided approach, we were able to optimize a 100 to 250 \u03bcM screening hit to a potent nanomolar inhibitor and lead compound, Mpro61. In this study, we further evaluate Mpro61 as a lead compound, starting with examination of its mode of binding to SARS-CoV-2 M\n                    <jats:sup>pro<\/jats:sup>\n                    . In vitro pharmacological profiling established a lack of off-target effects, particularly CYP450 3A4 inhibition, as well as potential for synergy with the currently approved alternate antiviral, molnupiravir. Development and subsequent testing of a capsule formulation for oral dosing of Mpro61 in B6-K18-hACE2 mice demonstrated favorable pharmacological properties, efficacy, and synergy with molnupiravir, and complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2320713121","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T15:06:53Z","timestamp":1713193613000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":17,"title":["Proof-of-concept studies with a computationally designed M\n                    <sup>pro<\/sup>\n                    inhibitor as a synergistic combination regimen alternative to Paxlovid"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6098-4959","authenticated-orcid":false,"given":"Christina","family":"Papini","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7760-8693","authenticated-orcid":false,"given":"Irfan","family":"Ullah","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06520-8066"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3641-7751","authenticated-orcid":false,"given":"Amalendu P.","family":"Ranjan","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Genetics Graduate School for Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06520-8066"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9677-9017","authenticated-orcid":false,"given":"Qihao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Yale University, New Haven, CT 06520-8107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8232-0239","authenticated-orcid":false,"given":"Krasimir A.","family":"Spasov","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4579-9202","authenticated-orcid":false,"given":"Chunhui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Yale University, New Haven, CT 06520-8107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3367-7240","authenticated-orcid":false,"given":"Walther","family":"Mothes","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06520-8066"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7583-1242","authenticated-orcid":false,"given":"Jason M.","family":"Crawford","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Yale University, New Haven, CT 06520-8107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett D.","family":"Lindenbach","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06520-8066"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7236-858X","authenticated-orcid":false,"given":"Pradeep D.","family":"Uchil","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06520-8066"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6901-5601","authenticated-orcid":false,"given":"Priti","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06520-8066"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3993-9520","authenticated-orcid":false,"given":"William 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