Development and Application of Small Molecule-Peptide Conjugates as Cathepsin K-Specific Covalent Irreversible Inhibitors in Human Osteoclast and Lung Cancer.

ABSTRACT: Cathepsin K (CTSK), a proteolytic enzyme that degrades the extracellular matrix, is recognized as a significant therapeutic target for osteoporosis, osteoarthritis, and rheumatoid arthritis. Due to adverse effects, no clinically approved drugs exist for CTSK. In order to develop safer therapeutics, highly selective CTSK inhibitors are required to elucidate the origins of side effects. Here, we developed various hybrid inhibitors by combining peptide sequences with small organic molecules. An acyloxymethyl ketone electrophile was incorporated as a bioisostere of the glycine-glycine cleavage site and inverse peptide sequences to enhance prime site interactions, as seen in the crystal structure. Additionally, a diphenyl group was incorporated to improve nonprime site interactions, culminating

SUBMITTER: Dey G 

PROVIDER: S-EPMC11938014 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature