Abstract
Tumor angiogenesis, essential for cancer development, is regulated mainly by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs), which are overexpressed in cancer cells. Therefore, the VEGF/VEGFR interaction represents a promising pharmaceutical target to fight cancer progression. The VEGF surface interacting with VEGFRs comprises a short α-helix. In this work, helical oligopeptides mimicking the VEGF-C helix were rationally designed based on structural analyses and computational studies. The helical conformation was stabilized by optimizing intramolecular interactions and by introducing helix-inducing Cα,α-disubstituted amino acids. The conformational features of the synthetic peptides were characterized by circular dichroism and nuclear magnetic resonance, and their receptor binding properties and antiangiogenic activity were determined. The best hits exhibited antiangiogenic activity in vitro at nanomolar concentrations and were resistant to proteolytic degradation.
Highlights
Angiogenesis—i.e., the formation of new blood vasculature from the established blood vessel network—can be associated to both physiological and pathological processes
We started our analysis from this complex, because all currently approved antiangiogenic drugs are targeted to vascular endothelial growth factors (VEGFs)-A or to vascular endothelial growth factor receptors (VEGFRs)-1
Several peptides able to bind to VEGFRs have been reported in the literature
Summary
Angiogenesis—i.e., the formation of new blood vasculature from the established blood vessel network—can be associated to both physiological and pathological processes (e.g., inflammation, tumor growth, and metastasis). Among the latter, tumor angiogenesis is essential for cancer development, since neovascularization provides a steady supply of oxygen and nutrients, supporting the proliferation of cancer cells (Mizejewski, 1999; Danhier et al, 2012; Johannessen et al, 2013). Angiogenic processes are mediated by cross-talk mechanisms that trigger direct association and cluster formation between specific receptors.
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