Inhibition of thrombosis by a selective fibrinogen receptor antagonist without effect on bleeding time.
Membrane glycoprotein alpha IIb beta 3 on platelets plays a pivotal role in hemostasis by mediating RGD-(arginine-glycine-aspartic acid)-dependent platelet adhesion and aggregation. Antagonists of alpha IIb beta 3 ligand binding function, such as antibodies, snake venom peptides, or synthetic RGD-containing peptides can completely inhibit platelet aggregation in vitro and cause significant prolongation of bleeding times when injected into experimental animals. The in vitro and in vivo properties of an alpha IIb beta 3 specific RGD-containing peptide 2G (G(Pen)GHRGDLRCA) were compared to two non-specific RGD-containing peptides 1N (G(Pen)GRGDTPCA) and 2H (GRGDSPDG). All three peptides have similar IC50 values in human platelet aggregation (14-22 microM) and ELISA-based alpha IIb beta 3 receptor assays (0.2-0.3 microM) but show different inhibitory activity (IC50 values) in the alpha v beta 5 (2G = 10 microM; 1N = 0.06 microM; 2H = 0.05 microM) and alpha 5 beta 1 receptor assays (2G = 8.3 microM; 1N = 0.06 microM; 2H = 0.04). The alpha IIb beta 3 specific peptide 2G had no effect on monolayers of human saphenous vein endothelial cells while 1N and 2H caused many cells to detach and contract. Peptides 2G and 1N inhibited ADP-stimulated ex vivo platelet aggregation in dogs in a dose dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)
Tschopp
J F
JF
Telios Pharmaceuticals, Inc., San Diego, CA 92121.
Mazur
C
C
Gould
K
K
Connolly
R
R
Pierschbacher
M D
MD
D000595:Amino Acid Sequence; D000818:Animals; D001760:Bleeding Time; D001808:Blood Vessels / Q000637:transplantation; D004285:Dogs; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010215:Papio; D010455:Peptides / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000517:prevention & control*
D010455:Peptides; D010980:Platelet Membrane Glycoproteins