# Chirality and Rigidity in Triazole-Modified Peptidomimetics Interacting with Neuropilin-1

## TL;DR

This paper explores how modifying peptides with triazole can improve their ability to block a protein interaction linked to cancer growth.

## Contribution

New triazole-modified peptidomimetics with enhanced rigidity and higher activity against Neuropilin-1/VEGF complex formation are developed.

## Key findings

- Triazole-modified peptidomimetics show greater activity than less restricted versions.
- One new structure outperforms the reference peptide A7R in affinity.
- Restricting the dihedral angle range of the backbone improves inhibitor performance.

## Abstract

The interaction of Neuropilin-1 (NRP-1) with vascular endothelial growth factor (VEGF) has been shown to promote angiogenesis under physiological and pathological conditions. Angiogenesis around tumors is a major factor allowing for their growth and spread. Disrupting NRP-1/VEGF complex formation is thus a promising pathway for the development of new anticancer pharmaceuticals. A large body of work has been produced in the last two decades detailing the development of inhibitors of NRP-1/VEGF complex formation. Among those were peptide A7R and its smaller derivatives KXXR and K(Har)XXR. It has been previously reported that replacement of the XX backbone with triazole residues has a positive effect on the proteolytic stability of inhibitors. It has also been reported that a higher dihedral angle range restriction of the XX backbone has a positive effect on the activity of inhibitors. In this work, we have designed new triazole derivatives of K(Har)XXR inhibitors with substitution allowing for higher range restriction of the XX backbone. The obtained peptidomimetics have greater activity than their less restricted counterparts. One of the newly obtained structures has greater affinity than the reference peptide A7R.