title: Vipegitide: a folded peptidomimetic partial antagonist of α2β1 integrin with antiplatelet aggregation activity.
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.
authors.affiliation: School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Momic
authors.affiliation: School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Jehoshua
authors.initials: J
authors.lastname: Katzhendler
authors.affiliation: Department of Hematology, Coagulation Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ela
authors.initials: E
authors.lastname: Shai
authors.affiliation: Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Noy
authors.affiliation: Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Hanoch
authors.initials: H
authors.lastname: Senderowitz
authors.affiliation: Institute for Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Eble
authors.affiliation: Department of Bioengineering, College of Engineering, Temple University, Philadelphia, PA, USA.
authors.forename: Cezary
authors.initials: C
authors.lastname: Marcinkiewicz
authors.affiliation: Department of Hematology, Coagulation Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Varon
authors.affiliation: School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Philip
authors.initials: P
authors.lastname: Lazarovici
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D006801:Humans; D038982:Integrin alpha2beta1 / Q000037:antagonists & inhibitors*; D020014:K562 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D057786:Peptidomimetics / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D038982:Integrin alpha2beta1; D010455:Peptides; D057786:Peptidomimetics; C000605634:vipegitide; D011092:Polyethylene Glycols
keywords: adhesion; collagen I; integrin antagonist; peptidomimetic; platelets