Vimocin and Vidapin, Cyclic KTS Peptides, are Dual, Partial Antagonists of α1β1/α2β1 Integrins with Antiangiogenic Activity

Reciprocal interactions between tumor and stromal cells with the extracellular matrix (ECM) collagens are involved in cancer progression and metastasis through interactions with integrins. Snake venom disintegrins are important tools in cancer research because they inhibit integrins with relative selectivity. The short disintegrins Viperistatin, is a 41 amino acids polypeptide, containing the characteristic three amino acid KTS motif, which is present in the loop conformation required for integrin binding.This disintegrin binds selectively α1β1integrin, in contrast to partial selectivity of RGD disintegrins. Viperistatin served as lead compound for the synthesis of linear and cyclic peptides containing the KTS motif in conformational constraint by cyclization via disulfide bridges. Vimocin and Vidapin showed a high potency (IC50 = 0.17 nM) and intermediate efficacy (20 and 40%) in inhibition of adhesion of α1/α2 integrin overexpressor cells to respective collagens. Vimocin was more active in inhibition of the wound healing (53%) and corneal micropocket vascularization (17%), whereas Vidapin was more potent in inhibition of migration in the Matrigel tube formation assay (90%). Both compounds similarly inhibited proliferation (50–90%) of endothelial cells, and angiogenesis induced by VEGF (80%) and glioma (55%) in the CAM assay. These peptides were not toxic to endothelial cells, acutely tolerated upon intravenous injection in mice, and were stable for 10–30 hours in human serum. Vimocin and Vidapin can be further exploited for drug development and may also serve as tools for investigations into α1β1/α2β1 biological function in angiogenesis and cancer.

* P.L. holds the Jacob Gitlin Chair in Physiology, and is affiliated and partially supported by the Hebrew University of Jerusalem Grass Center for Drug Design and Synthesis of Novel Therapeutics.