Rational Design of Anti-Angiogenic Peptides to Inhibit VEGF/VEGFR2 Interactions for Cancer Therapeutics

Author(s):

Samaneh Ghasemali, Safar Farajnia*, Abolfazl Barzegar*, Mohammad Rahmati, Babak Negahdari, Leila Rahbarnia and Hamidreza Yousefi-Nodeh   Pages 2026 - 2035 ( 10 )

Abstract:

<p>Background: Angiogenesis is a critical physiological process that plays a key role in tumor progression, metastatic dissemination, and invasion. In the last two decades, the vascular endothelial growth factor (VEGF) signaling pathway has been the area of extensive researches. VEGF executes its special effects by binding to vascular endothelial growth factor receptors (VEGFRs), particularly VEGFR-2. <p> Objective: The inhibition of VEGF/VEGFR2 interaction is known as an effective cancer therapy strategy. The current study pointed to design and model an anti-VEGF peptide based on VEGFR2 binding regions. <p> Methods: The large-scale peptide mutation screening was used to achieve a potent peptide with high binding affinity to VEGF for possible application in inhibition of VEGF/VEGFR2 interaction. The AntiCP and Peptide Ranker servers were used to generate the possible peptides library with anticancer activities and prediction of peptides bioactivity. Then, the interaction of VEGF and all library peptides were analyzed using Hex 8.0.0 and ClusPro tools. A number of six peptides with favorable docking scores were achieved. All of the best docking scores of peptides in complexes with VEGF were evaluated to confirm their stability, using molecular dynamics simulation (MD) with the help of the GROMACS software package. <p> Results: As a result, two antiangiogenic peptides with 13 residues of PepA (NGIDFNRDFFLGL) and PepC (NGIDFNRDKFLFL) were achieved and introduced to inhibit VEGF/VEGFR2 interactions. <p> Conclusion: In summary, this study provided new insights into peptide-based therapeutics development for targeting VEGF signaling pathway in tumor cells. PepA and PepC are recommended as potentially promising anticancer agents for further experimental evaluations.</p>

Keywords:

Angiogenesis, bioinformatics tools, peptide design, VEGF-A, VEGFR-2, molecular dynamics simulation.

Affiliation:

Department of Medical Biotechnology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Research Center of Bioscience and Biotechnology, University of Tabriz, Tabriz, Department of Clinical Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Research Center for Evidence-Based Medicine, Tabriz University of Medical Sciences, Tabriz

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