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Drug Design, Development and Therapy Volume 9, 2015 - Issue
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Original Research

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

Tatjana Momic1 School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
,
Jehoshua Katzhendler1 School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
,
Ela Shai2 Department of Hematology, Coagulation Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
,
Efrat Noy3 Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel
,
Hanoch Senderowitz3 Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel
,
Johannes A Eble4 Institute for Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany
,
Cezary Marcinkiewicz5 Department of Bioengineering, College of Engineering, Temple University, Philadelphia, PA, USA
,
David Varon2 Department of Hematology, Coagulation Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
&
Philip Lazarovici1 School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, IsraelCorrespondence[email protected]
 show all
Pages 291-304 | Published online: 05 Jan 2015

Figures & data

Figure 1 Synthesized peptides.

Notes: Chemical structure of (A) Pht-PEG2 unit, (B) Vipegitide, and (C) Vipegitide-PEG2.
Abbreviations: AIB, α-aminoisobutyric acid; PEG, polyethylene glycol; Pht, phthalimide.
Figure 1 Synthesized peptides.

Figure 2 Stability of Vipegitide-PEG2 in human serum.

Notes: Chromatograms of Vipegitide-PEG2 after 0, 60, and 120 minutes of incubation in human serum.
Abbreviation: PEG, polyethylene glycol; min, minutes.
Figure 2 Stability of Vipegitide-PEG2 in human serum.

Figure 3 Modeling of peptidomimetics in water.

Notes: Conformational space sampled by (A) Vipegitide and (B) Vipegitide-PEG2 peptidomimetics are represented by nine evenly spread snapshots taken from the last 400 snapshots collected during the simulation. Snapshots are shown as solid ribbons with residues colored according to secondary structure, ie, helices are red, beta sheets are cyan, turns are green, and coils are white. The two PEG molecules and lysineCitation3 of Vipegitide-PEG2 are shown as lines. Atoms N, C1, C2 in the N-terminus of Vipegitide-PEG2 are shown in ball and stick representation; (C) Histogram of the radii of gyration of Vipegitide (black) and Vipegitide-PEG2 (white) along the simulation. Please note that Vipegitide adopts a larger range of values, indicating that it is somewhat more flexible than Vipegitide-PEG2.
Abbreviation: PEG, polyethylene glycol.
Figure 3 Modeling of peptidomimetics in water.

Figure 4 Inhibitory effect of the peptidomimetics on α2 overexpressing cells and GST-A domain adhesion.

Notes: Dose response curves of the inhibition of α2 (open symbols) and α1 (solid symbols) cell adhesion to respective collagens (A) Vipegitide and (B) Vipegitide-PEG2; (C) binding of the GST-α1A domain to CB3 (collagen IV fragment) (solid symbols); and the GST-α2A domain to collagen I (open symbols) in the presence of Rhodocetin (triangle), Vixapatin (square), Vipegitide (circle), and Vipegitide-PEG2 (rhombus). The mean number of adherent cells ± SD is derived from three independent experiments.
Abbreviations: GST, glutathione s-transferase; PEG, polyethylene glycol; SD, standard deviation.
Figure 4 Inhibitory effect of the peptidomimetics on α2 overexpressing cells and GST-A domain adhesion.

Figure 5 The effect of the peptidomimetics on human and mouse platelet adhesion under flow conditions.

Notes: Surface coverage of (A) human and (B) mouse blood samples incubated with saline (control), 1 μg/mL collagen I (collagen I), 35 μM Vipegitide, or 35 μM Vipegitide-PEG2 and collagen I (Vipegitide, Vipegitide-PEG2) before applying shear stress; *,**P<0.05.
Abbreviation: PEG, polyethylene glycol.
Figure 5 The effect of the peptidomimetics on human and mouse platelet adhesion under flow conditions.

Figure 6 Effect of the peptidomimetics on ADP-activated aggregation of human platelets in PRP.

Notes: *Marks the point in time when the agonist (ADP) was added to the reaction. Aggregation tracing for 0 μM (red), 1.5 μM (green), and 2.5 μM (blue) of (A) Vipegitide and (B) Vipegitide-PEG2.
Abbreviations: ADP, adenosine diphosphate; PEG, polyethylene glycol; PRP, platelet rich plasma.
Figure 6 Effect of the peptidomimetics on ADP-activated aggregation of human platelets in PRP.

Figure 7 Effect of the peptidomimetics on collagen I-induced aggregation of platelets in PRP.

Notes: Platelet aggregation inhibited by (A) Vipegitide and (B) Vipegitide-PEG2; *P<0.05.
Abbreviations: PEG, polyethylene glycol; PRP, platelet rich plasma.
Figure 7 Effect of the peptidomimetics on collagen I-induced aggregation of platelets in PRP.

Figure 8 Effect of the peptidomimetics on collagen I-induced aggregation of human platelets in whole blood.

Notes: Platelet aggregation inhibited by (A) Vipegitide and (B) Vipegitide-PEG2; *P<0.05.
Abbreviation: PEG, polyethylene glycol.
Figure 8 Effect of the peptidomimetics on collagen I-induced aggregation of human platelets in whole blood.

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