Snake venoms comprise disintegrins, proteins which target integrin
receptor-dependent cell adhesion by endothelial cells. The disintegrins Obtustatin and
Viperistatin, were used as lead compounds for the synthesis of linear and cyclic
peptides containing the KTS binding motif. The most active linear peptide pointed to
the importance of Cys19 and Cys29, and the presence of Arg24 for biological activity,
and was used as the basic linear sequence for the synthesis of cyclic peptides. The most
potent peptides, named Vimocin and Vidapin, showed a high potency (IC50 = 0.17 nM)
and intermediate efficacy (20% and 40%) in inhibiting adhesion of α1/α2 integrinoverexpressing
cells to collagen. Vimocin was more active in inhibiting wound healing
and corneal micropocket vascularization, whereas Vidapin was more potent in reducing
endothelial cell migration in the Matrigel tube assay. Both compounds similarly
inhibited proliferation of endothelial cells and angiogenesis induced by vascular
endothelial growth factor or glioma tumor cells in the chorioallantoic membrane
angiogenic assay. These peptides were well tolerated by mice after intravenous injection. They showed stability in human serum between 10–30 hours. The in vitro
and in vivo potency of these cyclic peptides is consistent with the computational
modeling indicating conformational similarities to the parental molecules. Vidapin
significantly increased the survival of mice injected with B16 melanoma cells up to 73
days, whereas the median survival time of animals in this tumor experimental model is
40 days. These findings propose that Vimocin and Vidapin can serve as dual
α1β1/α2β1 integrin antagonists in angiogenesis and cancer therapy.
Keywords: Adhesion, Antiangiogenic, Anticancer, Conformation, Cyclic,
Disintegrin, Disulfide bond, Endothelial cell, Integrin, KTS motif, Lead
compound, Linear, Migration, Molecular dynamic simulations, Molecular
modeling, Partial antagonist, Peptides, Peptidomimetic, Proliferation, Stability.
