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

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Neuropilin-1 (NRP-1) interaction with vascular endothelial growth factor (VEGF) promotes tumor angiogenesis, crucial for cancer growth and metastasis.
• Disrupting the NRP-1/VEGF complex is a validated strategy for developing anti-cancer therapeutics.
• Previous inhibitors like peptide A7R and its derivatives (KXXR, K(Har)XXR) have been developed, with triazole substitutions improving stability and backbone restriction enhancing activity.

Purpose of the Study:

• To design novel triazole derivatives of K(Har)XXR inhibitors with restricted dihedral angles for the XX backbone.
• To evaluate the anti-angiogenic and anti-cancer potential of these new peptidomimetics.

Main Methods:

• Chemical synthesis of novel triazole-containing peptidomimetics based on the K(Har)XXR scaffold.
• Structural modification to achieve higher dihedral angle restriction in the XX backbone.
• In vitro assays to assess inhibitor activity and binding affinity.

Main Results:

• The newly designed triazole derivatives demonstrated enhanced inhibitory activity compared to less restricted analogs.
• One novel structure exhibited superior binding affinity to the NRP-1/VEGF complex compared to the reference peptide A7R.
• The modifications successfully increased the dihedral angle range restriction of the XX backbone.

Conclusions:

• Novel triazole derivatives of K(Har)XXR inhibitors with restricted backbones represent a promising class of anti-cancer agents.
• These compounds effectively inhibit NRP-1/VEGF interactions, thereby targeting tumor angiogenesis.
• Further development of these peptidomimetics could lead to new pharmaceuticals for cancer treatment.