The Peptide Glu-His-IIe-Pro-Ala Binds Fibrinogen and Inhibits Platelet Aggregation and Adhesion to Fibrinogen and Vitronectin

Abstract

Antiplatelet agents are clinically useful as antithrombotic entities. The importance of antiplatelet agents led us to design, synthesize, and characterize a new antiplatelet peptide. This peptide is a presumptive mimic of a ligand binding site on the platelet fibrinogen receptor. Unlike peptides related to Arg-Gly-Asp-Ser and His-His-Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val that bind to the fibrinogen receptor, this peptide binds to fibrinogen. The anticomplementarity hypothesis was used to design this presumptive peptide mimic of the vitronectin binding site on the fibrinogen receptor, glycoprotein IIb/IIIa complexes. The resulting peptide (Glu-His-Ile-Pro-Ala) has the characteristics of a fibrinogen binding site mimic: It binds fibrinogen and inhibits both the adhesion of platelets to fibrinogen and platelet aggregation. The peptide also inhibits the adhesion of platelets to vitronectin. The antiplatelet activity of this mimic peptide was dependent on its amino acid sequence, since closely related analogues were either inactive or less active inhibitors of platelet function than the original peptide. These results demonstrate that the peptide Glu-His-Ile-Pro-Ala has the characteristics expected of a mimic of a glycoprotein IIb/IIIa ligand binding site.

Sense–antisense (complementary) peptide interactions and the proteomic code; potential opportunities in biology and pharmaceutical science

“…(anti)-idiotypic antibodies [100,101] insulin [102] integrin [103] IFN-g [104] IFN-b [105] IL-1b IL-2 IL-18 [10,11,13,106,107] [108,109] [12] laminin receptor [110] luteinising hormone-releasing hormone [18,111] melanocyte stimulating hormone MHC II/peptide antigens [112] [113] trypsin-modulating oostatic factor [114] myelin basic protein neurokinin A/tachykinin NK1 receptor [33] [ 115] neurophysin II neutrophil chemoattractant nitric oxide synthase [77,116] [117] [118] ovine prolactin bovine P2 protein [119] [ 32] prion protein [120] ribonuclease S-peptide SARS-CoV protein [121,122] [ 36] somatostatin [123] substance P [23] T15 self-binding antibody thrombospondin-1/latency-associated peptide (LAP) TNF-a [26] [124] [125] vitronectin [93] (complementary) peptide mini-receptor inhibitors may be used to inhibit the aggregation of amyloid peptides, Ab, thereby significantly reducing Ab-mediated neurotoxicity [34]. Relatively recently, Imai et al demonstrated that HIV-1 infection can be modulated in vitro using antisense peptides that derive from internally complementary peptide sequences within the chemokine CCR5 receptor that otherwise participates with CD4 in mediating HIV-1 entry into white blood cells (leucocytes) [35].…”

“…[83] [84] c-Raf protein [48] cystatin-C/C4 [85] endothelin receptor EGFR human erythropoietin [86] [37] [87][88][89] [Met]-enkephalin [90][91][92] fibrinogen [93] fibronectin follicle-stimulating hormone [20,94] [ 95] g-endorphin [16,17] gastrin terminal peptide [96,97] growth hormone-releasing hormone T20 in gp160 of HIV [98] [99]…”