Nitro as a novel zinc-binding group in the inhibition of carboxypeptidase A

Abstract

2-Substituted 3-nitropropanoic acids were designed and synthesized as inhibitors against carboxypeptidase A (CPA). ( R)-2-Benzyl- 3-nitropropanoic acid showed a potent inhibition against CPA ( K i = 0.15 μM). X-ray crystallography discloses that the nitro group well mimics the transition state occurred in the hydrolysis catalyzed by CPA, that is, an O, O′-bidentate coordination to the zinc ion and the two respective hydrogen bonds with Glu-270 and Arg-127. Because the nitro group is a planar species, we proposed ( R)-2-benzyl-3-nitropropanoic acid as a pseudo-transition-state analog inhibitor against CPA.