Synthesis and structure-activity relationship of mannose-based peptidomimetics selectively blocking integrin alpha4beta7 binding to mucosal addressin cell adhesion molecule-1.
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.
Locardi
Elsa
E
Institut für Organische Chemie and Biochemie, Technische Universität München, Lichtenberg Strasse 4, 85747 Garching, Germany.
Boer
Jürgen
J
Modlinger
Armin
A
Schuster
Anja
A
Holzmann
Bernhard
B
Kessler
Horst
H
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
D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D016023:Integrins; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D010455:Peptides; C071777:integrin alpha4beta7; D008358:Mannose