loading page

Peptides derived from vascular endothelial growth factor B show potent binding to neuropilin-1 Short Title: VEGFB peptides bind to neuropilin-1.
  • +10
  • Filipa Mota,
  • Tamas Yelland,
  • Jennie Hutton,
  • Jennifer Parker,
  • Anastasia Patsiarika,
  • Edith Chan,
  • Andrew O'Leary,
  • Constantina Fotinou,
  • John Martin,
  • Ian Zachary,
  • Snezana Djordjevic,
  • Paul Frankel,
  • David Selwood
Filipa Mota
UCL
Author Profile
Tamas Yelland
UCL
Author Profile
Jennie Hutton
University College London
Author Profile
Jennifer Parker
UCL
Author Profile
Anastasia Patsiarika
UCL
Author Profile
Edith Chan
University College London
Author Profile
Andrew O'Leary
UCL
Author Profile
Constantina Fotinou
UCL
Author Profile
John Martin
UCL
Author Profile
Ian Zachary
UCL
Author Profile
Snezana Djordjevic
UCL
Author Profile
Paul Frankel
UCL
Author Profile
David Selwood
University College London

Corresponding Author:[email protected]

Author Profile

Abstract

Vascular endothelial growth factors (VEGF) regulate significant pathways in angiogenesis, myocardial and neuronal protection, metabolism, and cancer progression. There is growing evidence that 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). However the details of the interaction with NRP-1 and its functional importance have not been elucidated. We employed surface plasmon resonance technology and X-ray crystallography to characterize the direct binding 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. Results were compared with the corresponding VEGF-A derived peptides. Peptide lipidation was used as a means to stabilise the peptides. The binding of VEGF-B to NRP1-b1 was inhibited by a well characterized small molecule targeting the NRP1 arginine binding site. 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 – derived peptides containing a C-terminal arginine show potent binding to NRP1-b1 and inhibition of VEGF-A165 functional activity in HUVEC cells. Peptide lipidation increased binding residence time and improved plasma stability while maintaining binding affinity. The VEGF-B C-terminus imparts higher affinity for NRP-1 than the corresponding VEGF-A165 region. This binding is mediated through the canonical arginine site and the tight binding may impact on the activity and selectivity of the full-length protein. The VEGF-B167 derived peptides were more effective than VEGF-A165 peptides in blocking functional phosphorylation events.