Identification of SARS-CoV-2 M^pro inhibitors containing P1' 4-fluorobenzothiazole moiety highly active against SARS-CoV-2.

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^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^p

SUBMITTER: Higashi-Kuwata N 

PROVIDER: S-EPMC9958325 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature