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

• Published in: Journal of peptide science 1999-07, Vol.5 (7), p.313-322
• Main Authors: Peri, Francesco, Grell, Daniel, Dumy, Pascal, Yokokawa, Yoshihiro, Welzenbach, Karl, Weitz-Schmidt, Gabriele, Mutter, Manfred
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Cell Line; chemoselective ligation; Chromatography, High Pressure Liquid; constrained cyclic peptides; drug design; Magnetic Resonance Spectroscopy; Mass Spectrometry; Mice; Molecular Mimicry; Oligopeptides - chemistry; Oligopeptides - metabolism; Protein Binding; Protein Conformation; template assembly; Vascular Cell Adhesion Molecule-1 - chemistry; Vascular Cell Adhesion Molecule-1 - metabolism; VCAM-1 mimetics
• ISSN: 1075-2617; 1099-1387
• DOI: 10.1002/(SICI)1099-1387(199907)5:7<313::AID-PSC200>3.0.CO;2-F

The design and synthesis of cyclic mimetics of VCAM‐1 protein that reproduce the integrin‐binding domain are presented. The unprotected peptide precursor 37–43, Thr‐Gln‐Ile‐Asp‐Ser‐Pro‐Leu, was grafted onto functional templates of type naphthalene, biphenyl and benzyl through the chemoselective formation of C‐ and N‐terminal oximes resulting in a mixture of four isomeric forms due to syn–anti isomerism of the oxime bonds. Some isomers could be monitored by HPLC and identified by NMR. The molecule containing a naphthalene‐derived template was found to inhibit the VCAM‐1/VLA‐4 interaction more efficiently than previously reported for sulfur‐bridged cyclic peptides containing similar sequences. The finding confirms the importance of incorporating conformational constraints between the terminal ends of the peptide loop 37–43 in the design of synthetic inhibitors of the VCAM‐1/integrin interaction. Copyright © 1999 European Peptide Society and John Wiley & Sons, Ltd.