Transition State Analogy of Phosphonic Acid Peptide Inhibitors of Pepsin

Abstract

A series of 11 phosphonate peptide analogs, RO2C-Xaa-Yaa-Phe-{PO2-−O}-Phe O-(3-(4-pyridyl)propyl ester), were synthesized and evaluated as inhibitors of the aspartic peptidase pepsin. For the inhibitors with Gly or Ala at the P2 position, the Ki values correlate with the Km/kcat values of the corresponding substrates, demonstrating that these analogs mimic the transition state in the way the P2−P4 residues bind. Deviations from the correlation for the other inhibitor/substrate pairs imply a different binding orientation as a result of N-substitution at P2 (Pro), contamination with the more potent diastereomer (d-Ala), or a change in rate-limiting step for turnover (Ile).