| First Author | Higashi-Kuwata N | Year | 2023 |
| Journal | Nat Commun | Volume | 14 |
| Issue | 1 | Pages | 1076 |
| PubMed ID | 36841831 | Mgi Jnum | J:346851 |
| Mgi Id | MGI:7441447 | Doi | 10.1038/s41467-023-36729-0 |
| Citation | Higashi-Kuwata N, et al. (2023) Identification of SARS-CoV-2 M(pro) inhibitors containing P1' 4-fluorobenzothiazole moiety highly active against SARS-CoV-2. Nat Commun 14(1):1076 |
| abstractText | COVID-19 caused by SARS-CoV-2 has continually been serious threat to public health worldwide. While a few anti-SARS-CoV-2 therapeutics are currently available, their antiviral potency is not sufficient. Here, we identify two orally available 4-fluoro-benzothiazole-containing small molecules, TKB245 and TKB248, which specifically inhibit the enzymatic activity of main protease (M(pro)) 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 employing various target cells. Both compounds also block the replication of Delta and Omicron variants in human-ACE2-knocked-in mice. Native mass spectrometric analysis reveals that both compounds bind to dimer M(pro), apparently promoting M(pro) dimerization. X-ray crystallographic analysis shows that both compounds bind to M(pro)'s active-site cavity, forming a covalent bond with the catalytic amino acid Cys-145 with the 4-fluorine of the benzothiazole moiety pointed to solvent. The 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 anti-SARS-CoV-2 therapeutics. |
