Discovery of the Clinical Candidate <b>S-892216</b>: A Second-Generation of SARS-CoV-2 3CL Protease Inhibitor for Treating COVID-19.

ABSTRACT: The coronavirus disease 2019 (COVID-19) pandemic crisis has been mitigated by worldwide efforts to develop vaccines and therapeutic drugs. However, there remains concern regarding public health and an unmet need for therapeutic options. Herein, we report the discovery of S-892216, a second-generation SARS-CoV-2 3C-like protease (3CL^pro) inhibitor, to treat COVID-19. S-892216 is a reversible covalent 3CL^pro inhibitor with highly potent antiviral activity and an EC₅₀ value of 2.48 nM against SARS-CoV-2 infected cells. Structure-based design of a covalent modifier for compound 1 revealed that introducing a nitrile warhead increased 3CL^pro inhibition activity by 180-fold. Subsequent optimization efforts yielded S-892216, w

SUBMITTER: Unoh Y 

PROVIDER: S-EPMC12557365 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature