tLyp-1: A peptide suitable to target NRP-1 receptor.
Fiche publication
Date publication
octobre 2022
Journal
Bioorganic chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr FROCHOT Céline, Pr BOURA Cédric
Tous les auteurs :
Larue L, Kenzhebayeva B, Al-Thiabat MG, Jouan-Hureaux V, Mohd-Gazzali A, Wahab HA, Boura C, Yeligbayeva G, Nakan U, Frochot C, Acherar S
Lien Pubmed
Résumé
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.
Mots clés
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
Référence
Bioorg Chem. 2022 10 23;130:106200