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Starting with a lead-like dihydrouracil chemotype identified in a large-library docking campaign, we improved M\n                    <jats:sup>Pro<\/jats:sup>\n                    inhibition &gt;1000-fold by engaging additional M\n                    <jats:sup>Pro<\/jats:sup>\n                    subsites and using a latent electrophile to engage Cys\n                    <jats:sup>145<\/jats:sup>\n                    . Advanced leads from this series show pan-coronavirus antiviral activity, low clearance in mice, and for\n                    <jats:bold>AVI-4773<\/jats:bold>\n                    , a rapid reduction in viral titers &gt;1,000,000 after just three doses. Both compounds are well distributed in mouse tissues, including brain, where concentrations &gt;1000\u00d7 the 90% effective concentration are observed 8 hours after oral dosing for\n                    <jats:bold>AVI-4773<\/jats:bold>\n                    .\n                    <jats:bold>AVI-4516<\/jats:bold>\n                    shows minimal inhibition of major cytochrome P450s and human proteases.\n                    <jats:bold>AVI-4516<\/jats:bold>\n                    also exhibits synergy with the RNA-dependent RNA polymerase inhibitor, molnupiravir, in cellular infection models. Related analogs strongly inhibit nirmatrelvir-resistant M\n                    <jats:sup>Pro<\/jats:sup>\n                    mutant virus. The properties of this chemotype are differentiated from existing clinical and preclinical M\n                    <jats:sup>Pro<\/jats:sup>\n                    inhibitors and will advance therapeutic development against emerging SARS-CoV-2 variants and other coronaviruses.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adt7836","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T13:58:36Z","timestamp":1745416716000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":19,"title":["Structure-based discovery of highly bioavailable, covalent, broad-spectrum coronavirus M\n                    <sup>Pro<\/sup>\n                    inhibitors with potent in vivo efficacy"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4390-108X","authenticated-orcid":true,"given":"Tyler C.","family":"Detomasi","sequence":"first","affiliation":[{"name":"Department of 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