A Covalent Chemical Probe for <i>Chikungunya</i> nsP2 Cysteine Protease with Antialphaviral Activity and Proteome-wide Selectivity.

ABSTRACT: RA-0003022 (3) was identified as a high-quality covalent chemical probe for Chikungunya nsP2 cysteine protease (nsP2pro). Isoxazole 3 covalently captured the active site C478 and inactivated the enzyme with a k _inact/K _i ratio of 6000 M^-1s^-1. A negative control analog RA-0025453 (4) retained the covalent warhead but demonstrated >100-fold decrease in enzyme inhibition. Isoxazoles 3 and 4 were stable across a wide range of pH in solution and upon prolonged storage as solids. The covalent chemical probe 3 was inactive across a panel of 23 human and viral cysteine proteases and demonstrated remarkable proteome-wide selectivity by two chemoproteomic methods. Isoxazole 3 reduced vir

SUBMITTER: Ghoshal A 

PROVIDER: S-EPMC11601817 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature