Selwood, DL;
Mota, F;
Yelland, T;
Hutton, JA;
Parker, J;
Patsiarika, A;
Chan, AWE;
... Frankel, P; + view all
(2021)
Peptides Derived from Vascular Endothelial Growth Factor B Show Potent Binding to Neuropilin-1.
ChemBioChem
10.1002/cbic.202100463.
(In press).
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Selwood_Peptides derived from vascular endothelial growth factor B show potent binding to neuropilin-1_AOP.pdf - Published Version Download (2MB) | Preview |
Abstract
Vascular endothelial growth factors (VEGFs) regulate significant pathways in angiogenesis, myocardial and neuronal protection, metabolism, and cancer progression. The VEGF-B isoform is involved in cell survival, anti-apoptotic and antioxidant mechanisms, through binding to VEGF receptor 1 and neuropilin-1 (NRP-1). We employed surface plasmon resonance technology and X-ray crystallography to analyse the molecular basis of the interaction between VEGF-B and the b1 domain of NRP-1, and developed VEGF-B - C-terminus derived peptides to be used as chemical tools for studying VEGF-B - NRP-1 related pathways. Peptide lipidation was used as a means to stabilise the peptides. VEGF-B - derived peptides containing a C-terminal arginine show potent binding to NRP1-b1. Peptide lipidation increased binding residence time and improved plasma stability. A crystal structure of a peptide with NRP-1 demonstrated that VEGF-B peptides bind at the canonical C-terminal Arginine binding site. VEGF-B C-terminus imparts higher affinity for NRP-1 than the corresponding VEGF-A_{165} region. This tight binding may impact on the activity and selectivity of the full-length protein. The VEGF-B_{167} derived peptides were more effective than VEGF-A_{165} peptides in blocking functional phosphorylation events. Blockers of VEGF-B function have potential applications in diabetes and non-alcoholic fatty liver disease.
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