Document Report Card

ID: ALA2021843

Journal: J Med Chem

Title: Small peptide inhibitors of acetyl-peptide hydrolase having an uncommon mechanism of inhibition and a stable bent conformation.

Authors: Sandomenico A, Russo A, Palmieri G, Bergamo P, Gogliettino M, Falcigno L, Ruvo M.

Abstract: Acyl peptide hydrolase (APEH) catalyzes the removal of acetyl-amino acids from the N-terminus of peptides and cytoplasmic proteins. Due to the role played in several diseases, and to the growing interest around N-terminal acetylation, studies on APEH structure, function, and inhibition are attracting an ever increasing attention. We have therefore screened a random tetrapeptide library, N-capped with selected groups, and identified a trifluoroacetylated tetrapeptide (CF(3)-lmph) which inhibits the enzyme with a K(i) of 24.0 ± 0.8 μM. The inhibitor is selective for APEH, shows an uncommon uncompetitive mechanism of inhibition, and in solution adopts a stable bent conformation. CF(3)-lmph efficiently crosses cell membranes, blocking the cytoplasmic activity of APEH; however, it triggers a mild pro-apoptotic effect as compared to other competitive and noncompetitive inhibitors. The unusual inhibition mechanism and the stable structure make the new compound a novel tool to investigate enzyme functions and a useful scaffold to develop more potent inhibitors.

CiteXplore: 22309188

DOI: 10.1021/jm2013375