title: Systematic analysis of a dipeptide library for inhibitor development using human dipeptidyl peptidase IV produced by a Saccharomyces cerevisiae expression system.
abstract: 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(i)=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.
authors.affiliation: Department of Food and Nutritional Sciences, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, Yada 52-1, Shizuoka 422-8526, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Hikida
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ito
authors.forename: Takayasu
authors.initials: T
authors.lastname: Motoyama
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kato
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Kawarasaki
mesh_terms: D000595:Amino Acid Sequence; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004151:Dipeptides / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry*; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D058977:Molecular Sequence Annotation; D019151:Peptide Library; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
chemical_list: D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D019151:Peptide Library; D018819:Dipeptidyl Peptidase 4