Vipegitide: a folded peptidomimetic partial antagonist of alpha 2 beta 1 integrin with antiplatelet aggregation activity

• Published in: Drug design, development and therapy Vol. 9; pp. 291 - 304
• Main Authors: Momic, Tatjana, Katzhendler, Jehoshua, Shai, Ela, Noy, Efrat, Senderowitz, Hanoch, Eble, Johannes A, Marcinkiewicz, Cezary, Varon, David, Lazarovici, Philip
• Format: Journal Article
• Language: English
• Published: 05.01.2015
• ISSN: 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 alpha 2 beta 1 integrin, with platelet aggregation-inhibiting activity, named Vipegitide. Vipegitide is a 13-amino acid, folded peptidomimetic molecule, containing two alpha -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 (710-10 M and 1.510-10 M, respectively) and intermediate efficacy (40% and 35%, respectively) as well as selectivity toward alpha 2 integrin in inhibition of adhesion of alpha 1/ alpha 2 integrin overexpressing cells toward respective collagens. Interaction of both peptidomimetics with extracellular active domain of alpha 2 integrin was confirmed in cell-free binding assay with recombinant alpha 2 A-domain. Integrin alpha 2 beta 1 receptor is found on the platelet membrane and triggers collagen-induced platelet aggregation. Vipegitide and Vipegitide-PEG2 inhibited alpha 2 beta 1 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.