Design and synthesis of novel cyclic RGD-containing peptides as highly potent and selective integrin alpha IIb beta 3 antagonists.
Utilizing conformational constraints in conjunction with various structural considerations, we have synthesized a series of cyclic disulfide peptides that are highly potent and selective antagonists for the platelet integrin alpha IIb beta 3 (GPIIb/IIIa). The affinities of the peptides for alpha IIb beta 3 were determined by platelet aggregation assays and an alpha IIb beta 3 ELISA. Their affinities for alpha 5 beta 1 and alpha v beta 5 integrins were also determined in respective ELISA assays. Structure-activity relationship studies suggest that R-G-D-Ar-R (Ar = hydrophobic residue) is the essential pharmacophore that is responsible for their high alpha IIb beta 3 binding affinity, very high selectivity, and distinct biological properties. One of these analogues, TP9201, has been shown to inhibit platelet-mediated thrombus formation without associated prolongation of template bleeding time. The arginine residue adjacent the carboxy terminus of the R-G-D-Ar sequence could function as the biological effector element that determines this distinct and unexpected biological property.
Cheng
S
S
Telios Pharmaceuticals, Inc., San Diego, California 92121.
Craig
W S
WS
Mullen
D
D
Tschopp
J F
JF
Dixon
D
D
Pierschbacher
M D
MD
D000595:Amino Acid Sequence; D001120:Arginine / Q000737:chemistry; D001665:Binding Sites; D003500:Cyclization; D003545:Cysteine / Q000737:chemistry; D004220:Disulfides / Q000138:chemical synthesis; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011392:Proline / Q000737:chemistry; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D004220:Disulfides; D016023:Integrins; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C047981:arginyl-glycyl-aspartic acid; D001120:Arginine; D011392:Proline; D003545:Cysteine