Discovery and characterization of a novel cyclic peptide that effectively inhibits ephrin binding to the EphA4 receptor and displays anti-angiogenesis activity

Xiaofeng Han; Yan Xu; Yilei Yang; Jingle Xi; Wang Tian; Srinivas Duggineni; Ziwei Huang; Jing An

doi:10.1371/journal.pone.0080183

Discovery and characterization of a novel cyclic peptide that effectively inhibits ephrin binding to the EphA4 receptor and displays anti-angiogenesis activity

PLoS One. 2013 Nov 12;8(11):e80183. doi: 10.1371/journal.pone.0080183. eCollection 2013.

Authors

Xiaofeng Han¹, Yan Xu, Yilei Yang, Jingle Xi, Wang Tian, Srinivas Duggineni, Ziwei Huang, Jing An

Affiliation

¹ Department of Pharmacology, SUNY Upstate Medical University, Syracuse, New York, United States of America ; SUNY Upstate Cancer Research Institute, Department of Pharmacology, State University of New York, Syracuse, New York, United States of America.

Abstract

The EphA4 receptor tyrosine kinase regulates a variety of physiological and pathological processes during neural development and the formation of tumor blood vessels; thus, it represents a new and promising therapeutic target. We used a combination of phage peptide display and computer modeling/docking approaches and discovered a novel cyclic nonapeptide, now designated TYY. This peptide selectively inhibits the binding of the ephrinA5 ligand with EphA4 and significantly blocks angiogenesis in a 3D matrigel culture system. Molecular docking reveals that TYY recognizes the same binding pocket on EphA4 that the natural ephrin ligand binds to and that the Tyr3 and Tyr4 side chains of TYY are both critical for the TYY/EphA4 interaction. The discovery of TYY introduces a valuable probe of EphA4 function and a new lead for EphA4-targeted therapeutic development.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / metabolism*
Angiogenesis Inhibitors / pharmacology
Binding Sites
Cell Survival / drug effects
Ephrins / chemistry
Ephrins / metabolism*
Human Umbilical Vein Endothelial Cells
Humans
Ligands
Molecular Docking Simulation
Neovascularization, Physiologic / drug effects
Neovascularization, Physiologic / physiology
Peptides, Cyclic / chemistry
Peptides, Cyclic / metabolism*
Peptides, Cyclic / pharmacology
Protein Binding / drug effects
Protein Conformation
Receptor, EphA4 / chemistry
Receptor, EphA4 / metabolism*

Substances

Angiogenesis Inhibitors
Ephrins
Ligands
Peptides, Cyclic
Receptor, EphA4

Grants and funding

This work was supported by the DoD grant W81 XWH-07-1-0462. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.