Structure-activity relationships of alphaIIb 313-320 derived peptide inhibitors of human platelet aggregation.
The alphaIIbbeta3 receptor, which is the most abundant receptor on the surface of platelets, can interact with a variety of adhesive proteins including fibrinogen, fibronectin and the von Willebrand factor. Fibrinogen binding on alphaIIbbeta3 is an event essential for platelet aggregation and thrombus formation. Mapping of the fibrinogen-binding domains on alphaIIb subunit suggested the sequence 313-332 as a possible binding site. This region was restricted to sequence alphaIIb 313-320 (Y313MESRADR320) using synthetic octapeptides overlapping by six residues. The YMESRADR octapeptide inhibits ADP-stimulated human platelets aggregation and binds to immobilized fibrinogen. In this study, we used the Ala scanning methodology within the sequence 313-320 aiming to evaluate the contribution of each amino acid in inhibiting platelet aggregation. It was found that the substitution of Y313, M314, E315 or S316 by A does not affect the activity of the parent octapeptide. The-RADR-motif seems to be the most essential for the biological activity of the alphaIIb 313-320 site. The conformational analysis of the YAESRADR, YMESAADR and YMESRAAR analogs by using NMR spectroscopy and distance geometry calculations revealed significant differences in their conformational states in DMSO-d6.
Stanica
Ruxandra Maria
RM
Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece.
Benaki
Dimitra
D
Rodis
Foteini I
FI
Mikros
Emmanuel
E
Tsoukatos
Dimokritos
D
Tselepis
Alexandros
A
Tsikaris
Vasilios
V
D001120:Arginine / Q000737:chemistry; D001224:Aspartic Acid / Q000737:chemistry; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009842:Oligopeptides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D040201:Platelet Membrane Glycoprotein IIb / Q000737:chemistry*; D011487:Protein Conformation; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013329:Structure-Activity Relationship; D014841:von Willebrand Factor / Q000737:chemistry
D039661:Integrin beta3; D009842:Oligopeptides; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D040201:Platelet Membrane Glycoprotein IIb; D014841:von Willebrand Factor; D001224:Aspartic Acid; C047981:arginyl-glycyl-aspartic acid; D001120:Arginine