Catalytic covalent inhibition of cyclooxygenase-1 by a biomimetic acyltransferase

Abstract

Covalent binding enzyme inhibitors have grown in acceptance in therapeutic discovery. Several recent examples of protein-targeting acyl-transfer catalysts covalently modify protein targets in cellular systems but generally do not affect protein function. In this study, a small molecule has been developed for the first time that can achieve catalytic covalent inhibition of the inflammatory response enzyme, cyclooxygenase-1, in cells using only endogenous acetyl-CoA as a co-substrate. By utilizing a catalytic inhibitor which can self-regenerate, a sustained inhibitory response is achieved in cells compared to the analogous non-catalytic covalent cyclooxygenase antagonist, acetylsalicylic acid (aspirin).

Keywords: Acyl-transfer catalysis; Catalytic covalent inhibitor; Covalent inhibitor; Cyclooxygenase; Protein acetylation.