Structure-activity relationship study of tetrapeptide inhibitors of the Vascular Endothelial Growth Factor A binding to Neuropilin-1 |
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| Affiliation: | 1. Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland;2. Department of Neuropeptides, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland;3. Université Paris 13, Sorbonne Paris Cité, INSERM U1125, 74 rue Marcel Cachin, 93017 Bobigny, France;1. Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, Warsaw, Poland;2. Department of Bioanalysis and Drug Analysis, Medicinal University of Warsaw, Warsaw, Poland;3. Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland;4. Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, Lodz, Poland;5. Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, Lodz, Poland;6. Laboratory of Radiopharmacy, Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, Lodz, Poland;1. Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, Italy;2. Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Turkey;3. Department of Medical, Oral and Biotechnological Science, University “G. d’Annunzio” of Chieti-Pescara, Italy;1. Department of Molecular and Cellular Biochemistry, Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA;2. Washington University School of Medicine, St. Louis, MO 63110, USA;3. Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA;1. The Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK;1. Centre for Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, 16 Dorodna Street, 03-195 Warsaw, Poland;2. Pharmaceutical Research Institute, 8 Rydygiera Street, 01-793 Warsaw, Poland;3. Nuclear Medicine Department, Medical University of Warsaw, 1a Banacha Street, 02-097 Warsaw, Poland |
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| Abstract: | Neuropilin-1 is considered as one of the key receptors responsible for signaling pathways involved in pathological angiogenesis necessary for tumor progression, therefore targeting of VEGF165 binding to NRP-1 could be a relevant strategy for antiangiogenic treatment. It was shown before that the VEGF165/NRP-1 interaction can be inhibited by short tetrapeptides with K/RXXR sequence.Here, we present a structure–activity relationship study of the systematic optimization of amino acid residues in positions 1–3 in the above tetrapeptides. All the 13 synthesized analogs possessed C-terminal arginine that is a necessary element for interaction with NRP-1. The obtained results of the inhibitory activity and modeling by molecular dynamics indicate that simultaneous interactions of the basic amino acid residues in position 1 and 4 (Arg) with Neuropilin-1 are crucial and their cooperation strongly affects the inhibitory activity. In addition, the binding strength is modulated by the flexibility of the peptide backbone (in the central part of the peptide), and the nature of the side chain of the amino acids at the second or third position. A dramatic decrease in the activity to the receptor is observed in flexible derivatives that are missing proline residues. The results described in this paper should prove useful for future studies aimed at establishing the best pharmacophore for inhibitors of VEGF165 binding to NRP-1. |
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| Keywords: | Angiogenesis Neuropilin-1 Conformational flexibility Molecular dynamics |
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