title: Synthesis and structure-activity relationship of mannose-based peptidomimetics selectively blocking integrin alpha4beta7 binding to mucosal addressin cell adhesion molecule-1.
abstract: As part of our ongoing research in the development of alpha4beta7 integrin antagonists, we are interested in peptidomimetics based on a rigid scaffold to allow the display of essential side chains in a suitable binding conformation while eliminating backbone amide bonds and therefore improving pharmacokinetic parameters of the drug. Except for a few examples, peptidomimetics scaffolds have only been moderately successful and often yield molecules that lack the potency of their peptide counterparts. However, we present herein a successful application of using a rigid scaffold. Starting from a mannopyranoside analogue previously discovered in our laboratory as an inhibitor of the alpha4beta1/vascular cell adhesion molecule interaction, a biased library of functionalized carbohydrates was developed. One compound emerged from this library as an active and selective antagonist toward the alpha4beta7/mucosal addressin cell adhesion molecule interaction. Conformational implications and the relevance of different pharmacophoric patterns will be discussed in order to explain the reverse selectivity and enhanced affinity.
authors.affiliation: Institut für Organische Chemie and Biochemie, Technische Universität München, Lichtenberg Strasse 4, 85747 Garching, Germany.
authors.forename: Elsa
authors.initials: E
authors.lastname: Locardi
authors.forename: Jürgen
authors.initials: J
authors.lastname: Boer
authors.forename: Armin
authors.initials: A
authors.lastname: Modlinger
authors.forename: Anja
authors.initials: A
authors.lastname: Schuster
authors.forename: Bernhard
authors.initials: B
authors.lastname: Holzmann
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
mesh_terms: D015815:Cell Adhesion Molecules; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry / Q000378:metabolism*; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008358:Mannose / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D018716:Molecular Mimicry; D009088:Mucoproteins / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D016023:Integrins; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D010455:Peptides; C071777:integrin alpha4beta7; D008358:Mannose