Development of therapeutics for SARS-CoV-2 infection

Division Of Basic Sciences - Nci

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Abstract

We identified two orally-available 4-fluoro-benzothiazole-containing small molecules, TKB245 and TKB248, which specifically inhibit the enzymatic activity of main protease (Mpro) of SARS-CoV-2 and significantly more potently block the infectivity and replication of various SARS-CoV-2 strains than nirmatrelvir, molnupiravir, and ensitrelvir in cell-based assays with various target cells. Both compounds also blocked the replication of Delta and Omicron variants in human-ACE2-knocked-in mice. Native mass spectrometric analysis revealed that predominantly two TKB245 molecules bind to dimer Mpro, apparently promoting Mpro dimerization, while mostly one TKB248 molecule binds to the enzyme, failing to promote the dimerization. X-ray crystallographic analysis showed that both TKB245 and TKB248 bind to the Mpro's active-site cavity, forming a covalent bond with the catalytic amino acid Cys-145 with the 4-fluorine atom of the benzothiazole moiety pointed to solvent (Higashi-Kuwata & Mitsuya et al. Nat Commun 2023). The present data suggest that TKB245 and TKB248 might serve as potential therapeutics for COVID-19 and shed light upon further optimization to develop more potent and safer therapeutics for treating SARS-CoV-2 infection.