Urea moiety as amide bond mimetic in peptide-like inhibitors of VEGF-A165/NRP-1 complex

doi:10.1016/j.bmcl.2019.07.016

Bioorganic & Medicinal Chemistry Letters

Volume 29, Issue 17, 1 September 2019, Pages 2493-2497

https://doi.org/10.1016/j.bmcl.2019.07.016 Get rights and content

Abstract

NRP-1 is an important co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2). Many reports suggested that NRP-1 might also serve as a separate receptor for VEGF-A₁₆₅ causing stimulation of tumour growth and metastasis. Therefore, compounds interfering with VEGF-A₁₆₅/NRP-1 complex triggered interest in the design of new molecules, including peptides, as anti-angiogenic and anti-tumour drugs. Here, we report the synthesis, affinity and stability evaluation of the urea-peptide hybrids, based on general Lys(hArg)-AA²-AA³-Arg sequence, where hArg residue was substituted by Arg urea unit. Such substitution does not substantially affected affinity of compounds for NRP-1 but significantly increased their proteolytic stability in plasma.

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Acknowledgments

This work was financially supported by Grant No. 2017/27/N/NZ7/02473 from Narodowe Centrum Nauki (National Science Centre, Poland). We thank COST Action CA15135: Multi-target paradigm for innovative ligand identification in the drug discovery process (MuTaLig), supported by COST (European Cooperation in Science and Technology) for a STSM grant that enabled AKP to work for one month at Imagine Institute in Paris. LC and MS analysis were partially done in Laboratory of Chemical Synthesis, CePT,

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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.
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Urea moiety as amide bond mimetic in peptide-like inhibitors of VEGF-A165/NRP-1 complex

Abstract

Graphical abstract

Section snippets

Acknowledgments

Cell

J Biol Chem

J Biol Chem

Cell

J. Biol. Chem.

J Biol Chem

J Biol Chem

Structure

J Biol Chem

Nucl Med Biol

Life Sci

J Biol Chem

Biochem Pharmacol

Biochem Biophys Res Commun

J Biol Chem

Bioorg Med Chem Lett

Eur J Med Chem

Cell Signal

Cancer Lett

Proc Natl Acad Sci USA

J Pathol

J Clin Oncol

FASEB J

Cancer Biol Ther

PLoS Biol

Urea moiety as amide bond mimetic in peptide-like inhibitors of VEGF-A₁₆₅/NRP-1 complex