Conformational latitude - activity relationship of KPPR tetrapeptide analogues toward their ability to inhibit binding of vascular endothelial growth factor 165 to neuropilin-1

Neuropilin-1 (NRP-1) has been found to be overexpressed in several kinds of malignant tumors, and it is postulated that in pathological angiogenesis, its interaction with the vascular endothelial growth factor 165 (VEGF(165)) leads to progression of tumor vascularization and growth. Herein, we present synthesis and in vitro evaluation of tetrapeptides with the general sequence KxxR, where xx represents two canonical amino acid residues or a single amino acid possessing hydrocarbon backbone. All synthesized compounds were found to be inhibitors of VEGF(165)/NRP-1 interactions. The rationale behind their design was to elucidate the relationship between the xx flexibility and their inhibitory activity. Detailed molecular dynamics simulations for all synthesized compounds have been performed. A clear and quantitative relationship was found in the peptide analogues: the more flexible is the xx, the less active the analogue is. But surprisingly, highly flexible peptidomimetics with non-natural amino acids (NH2-(CH2)(n)-COOH; n=4,5) residues used possessed higher inhibitory activity than it was expected. Our molecular dynamics study of inhibitor/NRP-1 complexes provides convincing explanations of divergence in the observed inhibitory activity; thus, it might give indication for design of the next generation NRP-1 inhibitors. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd.