Structure-activity relationship studies and biological properties evaluation of peptidic NRP-1 ligands: Investigation of N-terminal cysteine importance

Anna K Puszko; Piotr Sosnowski; Olivier Hermine; Gérard Hopfgartner; Yves Lepelletier; Aleksandra Misicka

doi:10.1016/j.bmc.2023.117482

Structure-activity relationship studies and biological properties evaluation of peptidic NRP-1 ligands: Investigation of N-terminal cysteine importance

Bioorg Med Chem. 2023 Oct 30:94:117482. doi: 10.1016/j.bmc.2023.117482. Epub 2023 Sep 22.

Authors

Anna K Puszko¹, Piotr Sosnowski², Olivier Hermine³, Gérard Hopfgartner⁴, Yves Lepelletier³, Aleksandra Misicka⁵

Affiliations

¹ Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland. Electronic address: apuszko@chem.uw.edu.pl.
² Department of Inorganic and Analytical Chemistry, University of Geneva, 24 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland; Department of Bioanalytics, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland.
³ Université Paris Cité, Imagine Institute, 24 boulevard Montparnasse, 75015 Paris, France; INSERM UMR 1163, Laboratory of Cellular and Molecular Basis of Normal Hematopoiesis and Hematological Disorders: Therapeutical Implications, 24 boulevard Montparnasse, 75015 Paris, France.
⁴ Department of Inorganic and Analytical Chemistry, University of Geneva, 24 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland.
⁵ Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland. Electronic address: misicka@chem.uw.edu.pl.

PMID: 37774449
DOI: 10.1016/j.bmc.2023.117482

Abstract

Neuropilin-1 (NRP-1) is a major co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2). It may also stimulate tumour growth and metastasis independently of VEGF-A₁₆₅. These functions make VEGF-A₁₆₅/NRP-1 complex formation and its inhibition of great interest, where NRP-1 is the target for which effective ligands are sought. Design of peptide-like inhibitors represent a strategy with great potential in the treatment of NRP-1-related disorders. Here, we present the synthesis, molecular modelling, structure-activity relationship studies as well as biological evaluation of peptides with the branched sequences H₂N-X-Lys(hArg)-Dab-Oic-Arg-OH and H₂N-Lys(X-hArg)-Dab-Oic-Arg-OH. Two of the designed peptides, in which Cys was inserted in X position, expressed high affinity (∼40 nM value) for NRP-1 and were resistant to enzymatic digestion in human serum. Moreover, peptide/NRP-1 complex promoted fast intracytoplasmic protein trafficking towards the plasma membrane in breast cancer cells. Our results suggest that these compounds might be good candidates for further development of VEGF-A₁₆₅/NRP-1 inhibitors.

Keywords: Neuropilin-1; Peptide ligands; Protein-ligand interaction; VEGF-A(165); VEGF-A(165)/NRP-1 complex.