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

Tatjana Momic, Jehoshua Katzhendler, Ela Shai, Efrat Noy, Hanoch Senderowitz, Johannes Aeble, Cezary Marcinkiewicz, David Varon, Philip Lazarovici

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)291-303
Number of pages13
JournalDrug Design, Development and Therapy
Volume9
DOIs
StatePublished - 5 Jan 2015

Bibliographical note

Publisher Copyright:
© 2015 Momic et al.

Funding

FundersFunder number
National Institutes of Health
National Cancer InstituteR01CA133262

    Keywords

    • Adhesion
    • Collagen I
    • Integrin antagonist
    • Peptidomimetic
    • Platelets

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