AUTHOR=Zanella Simone , Bocchinfuso Gianfranco , De Zotti Marta , Arosio Daniela , Marino Franca , Raniolo Stefano , Pignataro Luca , Sacco Giovanni , Palleschi Antonio , Siano Alvaro S. , Piarulli Umberto , Belvisi Laura , Formaggio Fernando , Gennari Cesare , Stella Lorenzo 

TITLE=Rational Design of Antiangiogenic Helical Oligopeptides Targeting the Vascular Endothelial Growth Factor Receptors

JOURNAL=Frontiers in Chemistry

VOLUME=7

YEAR=2019

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2019.00170

DOI=10.3389/fchem.2019.00170

ISSN=2296-2646

ABSTRACT=<p>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 C<sup>α,α</sup>-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 <italic>in vitro</italic> at nanomolar concentrations and were resistant to proteolytic degradation.</p>