Discovery of Cyclic Peptide Inhibitors Targeting PD-L1 for Cancer Immunotherapy

Area of Science:

• Immunology
• Biochemistry
• Medicinal Chemistry

Background:

• Blockade of the programmed cell death ligand-1 (PD-L1) and programmed cell death-1 (PD-1) interaction is a successful cancer immunotherapy strategy.
• Peptides offer advantages as immune checkpoint inhibitors but face challenges with stability and delivery.
• Cyclization of peptides can enhance their biological activity and stability.

Purpose of the Study:

• To discover cyclic anti-PD-L1 peptides with improved bioactivity using macrocyclization scanning.
• To evaluate the efficacy of these cyclic peptides in blocking PD-1/PD-L1 interaction and in vivo anti-tumor activity.

Main Methods:

• Macrocyclization scanning was employed to generate cyclic peptides targeting PD-L1.
• The PD-1/PD-L1 blocking activity of the cyclic peptides was assessed.
• In vivo anti-tumor activity of the optimized cyclic peptides was evaluated.

Main Results:

• Cyclic peptides exhibited up to a 34-fold improvement in PD-1/PD-L1 blocking activity compared to linear counterparts.
• The developed cyclic peptides demonstrated significant in vivo anti-tumor efficacy.
• Macrocyclization scanning proved effective in enhancing serum stability and bioactivity.

Conclusions:

• Macrocyclization scanning is a viable strategy for optimizing bioactive peptides, particularly for modulating protein-protein interactions.
• Cyclic anti-PD-L1 peptides represent a promising therapeutic approach for cancer immunotherapy.
• This methodology can be applied to improve other therapeutic peptides targeting protein-protein interactions.