Vipegitide: a folded peptidomimetic partial antagonist of α2β1 integrin with antiplatelet aggregation activity

• Published in: Drug design, development and therapy development and therapy, 2015-01, Vol.9 (default), p.291-304
• Main Authors: Momic, Tatjana, Katzhendler, Jehoshua, Shai, Ela, Noy, Efrat, Senderowitz, Hanoch, Eble, Johannes A, Marcinkiewicz, Cezary, Varon, David, Lazarovici, Philip
• Format: Article
• Language: English
• Subjects: Acids; Adenosine; Adenosine diphosphate; Adhesion; Agglomeration; Aggregation; Amino acids; Animals; Binding sites; Blood clots; Blood platelets; Blood Platelets - drug effects; Cell Adhesion - drug effects; Collagen; Collagen (type I); collagen I; Drug delivery systems; Drugs; FDA approval; Gene expression; Glycine; Glycoproteins; Humans; Integrin alpha2beta1 - antagonists & inhibitors; integrin antagonist; Intravenous administration; K562 Cells; Lead compounds; Mice; Mice, Inbred C57BL; Original Research; Peptides; Peptides - administration & dosage; Peptides - chemistry; Peptides - pharmacology; peptidomimetic; Peptidomimetics; Peptidomimetics - administration & dosage; Peptidomimetics - chemistry; Peptidomimetics - pharmacology; Pharmaceutical research; Platelet aggregation; Platelet Aggregation - drug effects; Platelets; Polyethylene glycol; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacology; Proteins; Residues; Selectivity; Shear stress; Structure-Activity Relationship; Tryptophan
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S72844

Linear peptides containing the sequence WKTSRTSHY were used as lead compounds to synthesize a novel peptidomimetic antagonist of α2β1 integrin, with platelet aggregation-inhibiting activity, named Vipegitide. Vipegitide is a 13-amino acid, folded peptidomimetic molecule, containing two α-aminoisobutyric acid residues at positions 6 and 8 and not stable in human serum. Substitution of glycine and tryptophan residues at positions 1 and 2, respectively, with a unit of two polyethylene glycol (PEG) molecules yielded peptidomimetic Vipegitide-PEG2, stable in human serum for over 3 hours. Vipegitide and Vipegitide-PEG2 showed high potency (7×10(-10) M and 1.5×10(-10) M, respectively) and intermediate efficacy (40% and 35%, respectively) as well as selectivity toward α2 integrin in inhibition of adhesion of α1/α2 integrin overexpressing cells toward respective collagens. Interaction of both peptidomimetics with extracellular active domain of α2 integrin was confirmed in cell-free binding assay with recombinant α2 A-domain. Integrin α2β1 receptor is found on the platelet membrane and triggers collagen-induced platelet aggregation. Vipegitide and Vipegitide-PEG2 inhibited α2β1 integrin-mediated adhesion of human and murine platelets under the flow condition, by 50%. They efficiently blocked adenosine diphosphate- and collagen I-induced platelet aggregation in platelet rich plasma and whole human blood. Higher potency of Vipegitide than Vipegitide-PEG2 is consistent with results of computer modeling of the molecules in water. These peptidomimetic molecules were acutely tolerated in mice upon intravenous bolus injection of 50 mg/kg. These results underline the potency of Vipegitide and Vipegitide-PEG2 molecules as platelet aggregation-inhibiting drug lead compounds in antithrombotic therapy.