Urea moiety as amide bond mimetic in peptide-like inhibitors of VEGF-A165/NRP-1 complex. Issue 17 (1st September 2019)

• Record Type: Journal Article
• Authors: Puszko, Anna K.; Sosnowski, Piotr; Pułka-Ziach, Karolina; Hermine, Olivier; Hopfgartner, Gérard; Lepelletier, Yves; Misicka, Aleksandra
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 17(2019)
• Page Start: 2493
• Page End: 2497
• Publication Date: 2019-09-01
• Subjects: ArgU arginine urea derivative -- Aze azetidine-2-carboxylic acid -- Dab 2, 4-diaminobutyric acid -- Dhp 3, 4-dehydroproline -- DIPEA N, N-diisopropylethylamine -- ELISA enzyme-linked immunosorbent assay -- Fmoc fluorenylmethyloxycarbonyl -- hArg homoarginine -- HATU 1-[bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo[4, 5-b]pyridinium 3-oxid hexafluorophosphate -- NRP-1 Neuropilin-1 -- Oic octahydroindole-2-carboxylic acid -- Pbf 2, 2, 4, 6, 7-pentamethyldihydrobenzofuran-5-sulfonyl -- SPS Solid-Phase Synthesis -- TIS triisopropylosilane -- VEGF vascular endothelial growth factor -- VEGF-R vascular endothelial growth factor receptor -- TFA trifluoroacetic acid -- TIS triisopropylsilane; Peptidomimetics -- Amide bond mimetic -- Neuropilin-1 -- VEGF-A165 -- Protein–ligand interaction; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.07.016
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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( h Arg)-AA 2 -AA 3 -Arg sequence, where h Arg 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.