Azapeptide-Based SARS-CoV-2 Main Protease Inhibitors: Design, Synthesis, Enzyme Inhibition, Structural Determination, and Antiviral Activity.

ABSTRACT: M^pro of SARS-CoV-2 plays a vital role in the replication and pathogenesis of virus. Additionally, its high conservation within the Coronaviridae family makes it an attractive therapeutic target for developing broad-spectrum agents. This study describes the design, synthesis, and structure-activity relationships of azapeptide-based SARS-CoV-2 M^pro inhibitors, leading to several compounds with nanomolar IC₅₀ values. Examples include 14r (IC₅₀ = 13.3 nM), 14s (IC₅₀ = 30.6 nM), 20a (TPG-20a, IC₅₀ = 28.0 nM), and 20g (IC₅₀ = 30.4 nM). Some compounds inhibit MERS-CoV and SARS-CoV-1 M^pro but not the human protease cathepsin L. Several inhibitors, such as 20a and

SUBMITTER: Flury P 

PROVIDER: S-EPMC12481482 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature