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

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

doi:10.3389/fchem.2019.00170

Frontiers in Chemistry (Mar 2019)

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

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

Affiliations

Simone Zanella: Department of Chemistry, University of Milan, Milan, Italy
Gianfranco Bocchinfuso: Department of Chemical Science and Technologies, University of Rome Tor Vergata, Rome, Italy
Marta De Zotti: Padova Unit, Department of Chemistry, Institute of Biomolecular Chemistry, CNR, University of Padova, Padova, Italy
Daniela Arosio: National Research Council, Institute of Molecular Science and Technologies, Milan, Italy
Franca Marino: Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy
Stefano Raniolo: Department of Chemical Science and Technologies, University of Rome Tor Vergata, Rome, Italy
Luca Pignataro: Department of Chemistry, University of Milan, Milan, Italy
Giovanni Sacco: Department of Chemistry, University of Milan, Milan, Italy
Antonio Palleschi: Department of Chemical Science and Technologies, University of Rome Tor Vergata, Rome, Italy
Alvaro S. Siano: Departamento de Química Organica, Facultad de Bioquímica y Ciencias Biologicas, Universidad Nacional del Litoral, Santa Fe, Argentina
Umberto Piarulli: Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy
Laura Belvisi: Department of Chemistry, University of Milan, Milan, Italy
Laura Belvisi: National Research Council, Institute of Molecular Science and Technologies, Milan, Italy
Fernando Formaggio: Padova Unit, Department of Chemistry, Institute of Biomolecular Chemistry, CNR, University of Padova, Padova, Italy
Cesare Gennari: Department of Chemistry, University of Milan, Milan, Italy
Cesare Gennari: National Research Council, Institute of Molecular Science and Technologies, Milan, Italy
Lorenzo Stella: Department of Chemical Science and Technologies, University of Rome Tor Vergata, Rome, Italy

DOI: https://doi.org/10.3389/fchem.2019.00170
Journal volume & issue: Vol. 7

Abstract

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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.

Published in Frontiers in Chemistry

ISSN: 2296-2646 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Science: Chemistry
Website: http://journal.frontiersin.org/journal/chemistry

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