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Identification of SARS-CoV-2 M pro inhibitors containing P1' 4-fluorobenzothiazole moiety highly active against SARS-CoV-2.
- Source :
-
Nature communications [Nat Commun] 2023 Feb 25; Vol. 14 (1), pp. 1076. Date of Electronic Publication: 2023 Feb 25. - Publication Year :
- 2023
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Abstract
- 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 <superscript>pro</superscript> ) 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 <superscript>pro</superscript> , apparently promoting M <superscript>pro</superscript> dimerization. X-ray crystallographic analysis shows that both compounds bind to M <superscript>pro</superscript> '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.<br /> (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 14
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 36841831
- Full Text :
- https://doi.org/10.1038/s41467-023-36729-0