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Publication Abstract from PubMed

We identified a 5-fluoro-benzothiazole-containing small molecule, TKB272, through fluorine-scanning of the benzothiazole moiety, which more potently inhibits the enzymatic activity of SARS-CoV-2's main protease (M(pro)) and more effectively blocks the infectivity and replication of all SARS-CoV-2 strains examined including Omicron variants such as SARS-CoV-2(XBB1.5) and SARS-CoV-2(EG.5.1) than two M(pro) inhibitors: nirmatrelvir and ensitrelvir. Notably, the administration of ritonavir-boosted nirmatrelvir and ensitrelvir causes drug-drug interactions warranting cautions due to their CYP3A4 inhibition, thereby limiting their clinical utility. When orally administered, TKB272 blocked SARS-CoV-2(XBB1.5) 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-2(E166V-P14)) readily emerged by passage 14; however, when propagated with TKB272, no variants emerged by passage 25. SARS-CoV-2(E166V) 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'-E166 interactions, thereby limiting nirmatrelvir's M(pro) inhibition but that TKB272 nevertheless forms a tight binding with M(pro)'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 M(pro) inhibitors.

An orally available P1'-5-fluorinated M(pro) inhibitor blocks SARS-CoV-2 replication without booster and exhibits high genetic barrier.,Higashi-Kuwata N, Bulut H, Hayashi H, Tsuji K, Ogata-Aoki H, Kiso M, Takamune N, Kishimoto N, Hattori SI, Ishii T, Kobayakawa T, Nakano K, Shimizu Y, Das D, Saruwatari J, Hasegawa K, Murayama K, Sukenaga Y, Takamatsu Y, Yoshimura K, Aoki M, Furusawa Y, Okamura T, Yamayoshi S, Kawaoka Y, Misumi S, Tamamura H, Mitsuya H PNAS Nexus. 2025 Jan 7;4(1):pgae578. doi: 10.1093/pnasnexus/pgae578. eCollection , 2025 Jan. PMID:39831159^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.