Systematic analysis of a dipeptide library for inhibitor development using human dipeptidyl peptidase IV produced by a Saccharomyces cerevisiae expression system
Systematic analysis of a dipeptide library for inhibitor development using human dipeptidyl peptidase IV produced by a Saccharomyces cerevisiae expression system
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DOI：
10.1016/j.bbrc.2012.12.073
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发表时间：
2013-01-25
影响因子：
3.1
通讯作者：
Kawarasaki, Yasuaki
中科院分区：
文献类型：
--
作者：
Hikida, Aya;Ito, Keisuke;Kawarasaki, Yasuaki
抑制人二肽基肽酶IV/CD26(HDPPIV)是一种公认的治疗2型糖尿病的方法。本研究建立了酿酒酵母hDPPIV胞外生产体系，为hDPPIV抑制剂的筛选奠定了基础。由于模拟hDPPIV底物的二肽是该蛋白的候选抑制剂，系统地测试了X-Ala或X-Pro二肽(其中X代表任何氨基酸)。根据第一次筛选的结果，对Trp-X二肽进行了第二次筛选。为了阐明P-1和P-2位的理化特性对hDPPIV抑制作用的影响，分析了二肽抑制活性与13个氨基酸指数的相关性。最有效的抑制二肽为Trp-Pro(K-1=0.04 mM)。一些氨基酸指数和hDPPIV底物结合部位的结构很好地解释了二肽抑制hDPPIV的方式。对双肽文库的系统分析所获得的信息为hDPPIV靶向药物和治疗2型糖尿病的功能食品的开发提供了重要线索。(C)2012 Elsevier Inc.保留所有权利。
The inhibition of human dipeptidyl peptidase IV/CD26 (hDPPIV) is an accepted treatment for type 2 diabetes. In this study, an extracellular production system of hDPPIV using Saccharomyces cerevisiae was established to facilitate the screening of hDPPIV inhibitors. As dipeptides that mimic the hDPPIV substrate are candidate inhibitors of this protein, X-Ala or X-Pro dipeptides (in which X represents any amino acid) were tested systematically. Based on the results obtained in the first screening, a second screening was performed for Trp-X dipeptides. To elucidate the manner via which the physicochemical features at the P-1 and P-2 positions contributed to the hDPPIV inhibitory effect, correlations between the inhibitory activity of dipeptides and 13 amino acid indices were analyzed. The most effective inhibitory dipeptide was Trp-Pro (K-1 = 0.04 mM). The mode of inhibition of hDPPIV by dipeptides was explained well by some amino acid indices and by the structure of the substrate-binding site of hDPPIV. The information obtained from the systematic analysis of a dipeptide library provides important clues for the development of hDPPIV targeting drugs and functional foods for type 2 diabetes. (C) 2012 Elsevier Inc. All rights reserved.