Assembly of binding loops on aromatic templates as VCAM-1 mimetics.
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.
Peri
F
F
Institute of Organic Chemistry, University of Lausanne, Switzerland.
Grell
D
D
Dumy
P
P
Yokokawa
Y
Y
Welzenbach
K
K
Weitz-Schmidt
G
G
Mutter
M
M
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D019010:Vascular Cell Adhesion Molecule-1 / Q000737:chemistry* / Q000378:metabolism
D009842:Oligopeptides; D019010:Vascular Cell Adhesion Molecule-1