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Here we report an \u03b1-ketoamide-based peptidomimetic inhibitor of the SARS-CoV-2 main protease (M\n                    <jats:sup>pro<\/jats:sup>\n                    ), designated RAY1216. Enzyme inhibition kinetic analysis shows that RAY1216 has an inhibition constant of 8.4\u2009nM and suggests that it dissociates about 12 times slower from M\n                    <jats:sup>pro<\/jats:sup>\n                    compared with nirmatrelvir. The crystal structure of the SARS-CoV-2 M\n                    <jats:sup>pro<\/jats:sup>\n                    :RAY1216 complex shows that RAY1216 covalently binds to the catalytic Cys145 through the \u03b1-ketoamide group. In vitro and using human ACE2 transgenic mouse models, RAY1216 shows antiviral activities against SARS-CoV-2 variants comparable to those of nirmatrelvir. It also shows improved pharmacokinetics in mice and rats, suggesting that RAY1216 could be used without ritonavir, which is co-administered with nirmatrelvir. RAY1216 has been approved as a single-component drug named \u2018leritrelvir\u2019 for COVID-19 treatment in China.\n                  <\/jats:p>","DOI":"10.1038\/s41564-024-01618-9","type":"journal-article","created":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T07:01:54Z","timestamp":1711695714000},"page":"1075-1088","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["Preclinical evaluation of the SARS-CoV-2 Mpro inhibitor RAY1216 shows improved pharmacokinetics compared with 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