Preclinical evaluation of the SARS-CoV-2 M^pro inhibitor RAY1216 shows improved pharmacokinetics compared with nirmatrelvir.

ABSTRACT: Although vaccines are available for SARS-CoV-2, antiviral drugs such as nirmatrelvir are still needed, particularly for individuals in whom vaccines are less effective, such as the immunocompromised, to prevent severe COVID-19. Here we report an α-ketoamide-based peptidomimetic inhibitor of the SARS-CoV-2 main protease (M^pro), designated RAY1216. Enzyme inhibition kinetic analysis shows that RAY1216 has an inhibition constant of 8.4 nM and suggests that it dissociates about 12 times slower from M^pro compared with nirmatrelvir. The crystal structure of the SARS-CoV-2 M^pro:RAY1216 complex shows that RAY1216 covalently binds to the catalytic Cys145 through the α-ketoamide group. In vitro and using human ACE2 transgenic mouse models, RAY1216 shows antiviral act

SUBMITTER: Chen X 

PROVIDER: S-EPMC10994847 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature