Structure-Guided Design of Cyclic Peptide: A Potent Inhibitor Targeting PD-1/PD-L1 Axis with Antitumor Activity

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• The programmed cell death protein 1 (PD-1) and its ligand PD-L1 pathway is a key target in cancer immunotherapy.
• Current monoclonal antibody therapies face challenges including high costs and limited tumor penetration.

Purpose of the Study:

• To develop a novel cyclic peptide inhibitor targeting the PD-1/PD-L1 interaction.
• To evaluate the efficacy and safety of the peptide inhibitor PD-1-0520 in preclinical cancer models.

Main Methods:

• Structure-based design of cyclic peptides based on PD-L1 fragments.
• Molecular dynamics screening, in vitro assays, and in vivo studies in tumor-bearing mice.
• Assessment of tumor inhibition, immune cell infiltration, and activation markers.

Main Results:

• PD-1-0520 demonstrated potent inhibition of the PD-1/PD-L1 interaction.
• The peptide achieved a 68% tumor inhibition rate in B16-F10 models without systemic toxicity.
• PD-1-0520 promoted CD8+ T cell infiltration and activation, remodeling the tumor immune microenvironment.

Conclusions:

• PD-1-0520 is a promising cyclic peptide inhibitor for cancer immunotherapy.
• The structure-based design strategy offers a novel approach for developing protein-protein interaction inhibitors.