Assembly of binding loops on aromatic templates as VCAM-1 mimetics

The design and synthesis of cyclic mimetics of VCAM-1 protein that reproduc e the integrin-binding domain are presented. The unprotected peptide precur sor 37-43, Thr-Gln-Ile-Asp-Ser-Pro-Leu, was grafted onto functional templat es of type naphthalene, biphenyl and benzyl through the chemoselective form ation of C- and N-terminal oximes resulting in a mixture of four isomeric f orms due to syn-anti isomerism of the oxime bonds. Some isomers could be mo nitored by HPLC and identified by NMR, The molecule containing a naphthalen e-derived template mas found to inhibit the VCAM-1/VLA-4 interaction more e fficiently than previously reported for sulfur-bridged cyclic peptides cont aining similar sequences. The finding confirms the importance of incorporat ing conformational constraints between the terminal ends of the peptide loo p 37-43 in the design of synthetic inhibitors of the VCAM-1/integrin intera ction. Copyright (C) 1999 European Peptide Society and John Wiley & Sons, L td.