title: Design and synthesis of potent and selective alpha(4)beta(7) integrin antagonists.
abstract: Interactions of the integrins alpha(4)beta(7) with its cognate ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1) play a crucial role in the development of mucosa-associated lymphoid organs, in the generation of mucosal immune responses, and in diverse pathological processes such as chronic inflammatory bowel disease and type I diabetes. Using a previously developed spatial screening technique we describe the development of potent and selective alpha(4)beta(7) integrin antagonists based on the domain 1 Leu-Asp-Thr (LDT) sequence of MAdCAM-1 that is essential for alpha(4)beta(7) integrin binding. A library of homodetic cyclic penta- and hexapeptides was synthesized presenting the pharmacophoric LDT-sequence in different conformations. The cyclic hexapeptide P10 cyclo(Leu-Asp-Thr-Ala-D-Pro-Ala) inhibits alpha(4)beta(7) integrin mediated cell adhesion to MAdCAM-1 effectively. Further optimization of the lead structure P10 resulted in cyclic hexapeptides with enhanced activity. The compounds P25 cyclo(Leu-Asp-Thr-Ala-D-Pro-Phe), P28 cyclo(Leu-Asp-Thr-Asp-D-Pro-Phe), P29 cyclo(Leu-Asp-Thr-Asp-D-Pro-His), and P30 cyclo(Leu-Asp-Thr-Asp-D-Pro-Tyr) strongly inhibited alpha(4)beta(7) integrin mediated cell adhesion to MAdCAM-1, but they did not affect binding of the closely related alpha(4)beta(1) integrin to VCAM-1.
authors.affiliation: Institut für Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Boer
authors.forename: D
authors.initials: D
authors.lastname: Gottschling
authors.forename: A
authors.initials: A
authors.lastname: Schuster
authors.forename: M
authors.initials: M
authors.lastname: Semmrich
authors.forename: B
authors.initials: B
authors.lastname: Holzmann
authors.forename: H
authors.initials: H
authors.lastname: Kessler
mesh_terms: D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules; D000090266:Chromobox Protein Homolog 5; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D015195:Drug Design; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry* / Q000378:metabolism; D066298:In Vitro Techniques; D016023:Integrins / Q000037:antagonists & inhibitors*; D019169:Jurkat Cells; D007797:Laminin / Q000378:metabolism; D008024:Ligands; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009088:Mucoproteins / Q000737:chemistry* / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C000715594:CBX5 protein, human; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D016023:Integrins; D007797:Laminin; D008024:Ligands; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D009842:Oligopeptides; D019151:Peptide Library; D010456:Peptides, Cyclic; C071777:integrin alpha4beta7; D000090266:Chromobox Protein Homolog 5