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Notably, the administration of ritonavir-boosted nirmatrelvir and ensitrelvir causes drug\u2013drug interactions warranting cautions due to their CYP3A4 inhibition, thereby limiting their clinical utility. When orally administered, TKB272 blocked SARS-CoV-2XBB1.5 replication without ritonavir in B6.Cg-Tg(K18-hACE2)2-Prlmn\/J-transgenic mice, comparably as did ritonavir-boosted nirmatrelvir. When the ancestral SARS-CoV-2 was propagated with nirmatrelvir in vitro, a highly nirmatrelvir-resistant E166V-carrying variant (SARS-CoV-2E166V\u2212P14) readily emerged by passage 14; however, when propagated with TKB272, no variants emerged by passage 25. SARS-CoV-2E166V showed some cross-resistance to TKB272 but was substantially sensitive to the compound. X-ray structural analyses and mass-spectrometric data showed that the E166V substitution disrupts the critical dimerization-initiating Ser1\u2032-E166 interactions, thereby limiting nirmatrelvir's Mpro inhibition but that TKB272 nevertheless forms a tight binding with Mpro's catalytic active sight even in the presence of the E166V substitution. TKB272 shows no apparent genotoxicity as tested in the micro-Ames test. Highly potent TKB272 may serve as a COVID-19 therapeutic, overcome resistance to existing Mpro inhibitors.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgae578","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T02:53:57Z","timestamp":1736218437000},"source":"Crossref","is-referenced-by-count":12,"title":["An orally available P1\u2032-5-fluorinated Mpro inhibitor blocks SARS-CoV-2 replication without booster and exhibits high genetic barrier"],"prefix":"10.1093","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9404-3532","authenticated-orcid":false,"given":"Nobuyo","family":"Higashi-Kuwata","sequence":"first","affiliation":[{"name":"Department of Refractory Viral Diseases, National Center for Global Health and Medicine Research Institute , 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655 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