tLyp-1: A peptide suitable to target NRP-1 receptor

Bioorg Chem. 2023 Jan:130:106200. doi: 10.1016/j.bioorg.2022.106200. Epub 2022 Oct 23.

Abstract

Targeting vascular endothelial growth factor receptor (VEFGR) and its co-receptor neuropilin-1 (NRP-1) is an interesting vascular strategy. tLyp-1 is a tumor-homing and penetrating peptide of 7 amino acids (CGNKRTR). It is a truncated form of Lyp-1 (CGNKRTRGC), which is known to target NRP-1 receptor, with high affinity and specificity. It is mediated by endocytosis via C-end rule (CendR) internalization pathway. The aim of this study is to evaluate the importance of each amino acid in the tLyp-1 sequence through alanine-scanning (Ala-scan) technique, during which each of the amino acid in the sequence was systematically replaced by alanine to produce 7 different analogues. In silico approach through molecular docking and molecular dynamics are employed to understand the interaction between the peptide and its analogues with the NRP-1 receptor, followed by in vitro ligand binding assay study. The C-terminal Arg is crucial in the interaction of tLyp-1 with NRP-1 receptor. Substituting this residue dramatically reduces the affinity of this peptide which is clearly seen in this study. Lys-4 is also important in the interaction, which is confirmed via the in vitro study and the MM-PBSA analysis. The finding in this study supports the CendR, in which the presence of R/K-XX-R/K motif is essential in the binding of a ligand with NRP-1 receptor. This presented work will serve as a guide in the future work pertaining the development of active targeting agent towards NRP-1 receptor.

Keywords: Alanine-scanning; H-bonds; In vitro ligand binding; MM-PBSA per residue energy decomposition; Molecular docking; Molecular dynamic; NRP–1; Radius of gyration (Rg); Targeting; tLyp-1 peptide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine
  • Amino Acids
  • Ligands
  • Molecular Docking Simulation
  • Neuropilin-1* / chemistry
  • Neuropilin-1* / metabolism
  • Peptides / chemistry
  • Vascular Endothelial Growth Factor A* / metabolism

Substances

  • Alanine
  • Amino Acids
  • Ligands
  • Neuropilin-1
  • Peptides
  • Vascular Endothelial Growth Factor A
  • tLyP-1 peptide