Modulation of the activity and assessment of the receptor selectivity in a series of new RGD-containing peptides.
We have investigated the structure-activity relationship of a series of new synthetic RGD analogs and their potential use as specific platelet aggregation inhibitors. Twelve short linear peptides showed high potency to inhibit aggregation in ADP-stimulated dog platelets. In order to assess the selectivity of these analogs towards platelet integrin GPIIb-IIIa, a new cell adhesion inhibition system was devised which was able to discriminate between the two closely related beta 3-integrins of the vasculature, GPIIb-IIIa (alpha IIb beta 3), present in platelets, and the vitronectin receptor (alpha v beta 3), expressed in endothelial cells and platelets. As reported for other peptides by Scarborough et al. (1993, J. Biol. Chem. 268, 1066), the analogs containing lysine instead of arginine in position 1 showed increased selectivity towards GPIIb-IIIa. One of them, in which the piperidine carboxylic group was attached to the N-terminus of KGDW, not only strongly inhibited platelet aggregation, but also selectively abolished cell adhesion mediated by GPIIb-IIIa without effect on the vitronectin receptor.
Fauchère
J L
JL
Servier Research Institute, Suresnes, France.
Morris
A D
AD
Thurieau
C
C
Simonet
S
S
Verbeuren
T J
TJ
Kieffer
N
N
D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D004285:Dogs; D006801:Humans; D016023:Integrins / Q000187:drug effects*; D008239:Lysine / Q000737:chemistry*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000494:pharmacology*; D016024:Receptors, Cytoadhesin / Q000187:drug effects*; D019030:Receptors, Vitronectin; D013329:Structure-Activity Relationship
D016023:Integrins; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D016024:Receptors, Cytoadhesin; D019030:Receptors, Vitronectin; D008239:Lysine