Structure-activity relationship study of tetrapeptide inhibitors of the Vascular Endothelial Growth Factor A binding to Neuropilin-1.
Neuropilin-1 is considered as one of the key receptors responsible for signaling pathways involved in pathological angiogenesis necessary for tumor progression, therefore targeting of VEGF165 binding to NRP-1 could be a relevant strategy for antiangiogenic treatment. It was shown before that the VEGF165/NRP-1 interaction can be inhibited by short tetrapeptides with K/RXXR sequence. Here, we present a structure-activity relationship study of the systematic optimization of amino acid residues in positions 1-3 in the above tetrapeptides. All the 13 synthesized analogs possessed C-terminal arginine that is a necessary element for interaction with NRP-1. The obtained results of the inhibitory activity and modeling by molecular dynamics indicate that simultaneous interactions of the basic amino acid residues in position 1 and 4 (Arg) with Neuropilin-1 are crucial and their cooperation strongly affects the inhibitory activity. In addition, the binding strength is modulated by the flexibility of the peptide backbone (in the central part of the peptide), and the nature of the side chain of the amino acids at the second or third position. A dramatic decrease in the activity to the receptor is observed in flexible derivatives that are missing proline residues. The results described in this paper should prove useful for future studies aimed at establishing the best pharmacophore for inhibitors of VEGF165 binding to NRP-1.
['Tymecka|Dagmara|D|', 'Lipiński|Piotr F J|PFJ|', 'Fedorczyk|Bartłomiej|B|', 'Puszko|Anna|A|', 'Wileńska|Beata|B|', 'Perret|Gerard Y|GY|', 'Misicka|Aleksandra|A|']
D020533:Angiogenesis Inhibitors D000818:Animals D006801:Humans D056004:Molecular Dynamics Simulation D039942:Neuropilin-1 D009842:Oligopeptides D051381:Rats D013329:Structure-Activity Relationship D042461:Vascular Endothelial Growth Factor A
Neuropilin-1 Angiogenesis Molecular dynamics Conformational flexibility VEGF(165)/NRP-1 inhibitors