Istituto di Biostrutture e Bioimmagini, CNR, via Mezzocannone 16, 80134, Napoli, Italy.
J Med Chem. 2012 Mar 8;55(5):2102-11. doi: 10.1021/jm2013375. Epub 2012 Feb 21.
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.
酰肽水解酶（APEH）催化从肽和细胞质蛋白的 N 末端去除乙酰氨基酸。由于其在几种疾病中发挥的作用，以及对 N 端乙酰化的日益关注，对 APEH 结构、功能和抑制作用的研究引起了越来越多的关注。因此，我们筛选了一个随机四肽库，并用选定的基团对其 N 端进行了封端，并鉴定出一种三氟乙酰化四肽（CF(3)-lmph），其对酶的抑制常数（Ki）为 24.0±0.8 μM。该抑制剂对 APEH 具有选择性，表现出一种不常见的非竞争性抑制机制，并且在溶液中采用稳定的弯曲构象。CF(3)-lmph 能够有效地穿过细胞膜，阻断 APEH 的细胞质活性；然而，与其他竞争性和非竞争性抑制剂相比，它会引发轻微的促凋亡作用。这种不寻常的抑制机制和稳定的结构使新化合物成为研究酶功能的新工具，也是开发更有效的抑制剂的有用支架。
