Design and Synthesis of Potent and Selective α₄β₇Integrin 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.

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

“…Structure-activity relationships can be derived and the bioactive conformation can be discovered upon screening future science group the library of peptides for their affinity to the receptor and structural ana lysis of the analog. The spatial screening concept was introduced by Kessler and co-workers in the early 1990s and has been elaborately used in the study of integrin binding of peptides via the RGD [96] or LDT sequence [97]. In this manner, selectively binding peptides could be developed by understanding more about the conformation of the ligand preferred by the receptor.…”

Modulation of Protein-Protein Interactions by Stabilizing/Mimicking Protein Secondary Structure Elements

“…Compound 16, as well as other analogues resulting from systematic exchange of amino acid residues while maintaining the backbone structure, effectively inhibited the α 4 β 7 integrin mediated cell adhesion to MAdCAM-1 [77]. A biased library of functionalized carbohydrates, as rigid scaffolds to allow the display of the essential side chains of peptide 16, resulted in the mannose-based antagonist 17, which mimicked the active conformation of the α 4 β 7 selective peptides [78].…”

Syntheses of Peptidomimetics Based on Pyranose and Polyhydroxylated Piperidine Scaffolds

“…The group initially designed a cyclic hexapeptide (72, Fig. (12)), which was found to have high selectivity for cell attachment via the α 4 ß 7 integrin [34]. The elucidation of the bioactive conformation of this peptide led them to replace the backbone by a β-D-mannose scaffold (73), which presented the pharmacophoric Leu-Asp-Thr side chain mimetics in similar spatial orientation.…”