Structure-Guided Virtual Screening of Small Peptide Inhibitors Targeting PD-L1 for Cancer Immunotherapy

Area of Science:

• Immunology
• Structural Biology
• Computational Chemistry

Background:

• The programmed cell death-1 (PD-1)/PD-L1 pathway is crucial for tumor immune evasion.
• Monoclonal antibodies targeting PD-1/PD-L1 have clinical benefits but face challenges with tumor penetration and immunogenicity.
• Small peptides offer potential advantages in tunability and tissue penetration for cancer immunotherapy.

Purpose of the Study:

• To identify small peptides that disrupt the PD-1/PD-L1 interaction using a structure-guided virtual screening approach.
• To develop novel peptide-based therapeutics as an alternative to antibody-based immunotherapies.
• To explore the potential of peptide scaffolds for modulating protein-protein interactions in cancer.

Main Methods:

• Structure-guided virtual screening of a peptide library.
• Alanine scanning mutagenesis to identify key binding residues.
• Molecular docking and dynamics simulations for hit selection.
• Experimental validation using ELISA and immune cell cocultures.

Main Results:

• Identified key binding residues for PD-1/PD-L1 interaction through alanine scanning.
• Designed and screened a virtual library of 24,423 small peptides.
• Validated potent peptide inhibitors, with lead peptide FJ15596 showing significant PD-1/PD-L1 binding inhibition (IC50 = 570 nM).
• Demonstrated restoration of CD3+ T cell viability in a cancer cell coculture model.

Conclusions:

• A structure-guided virtual screening strategy successfully identified potent peptide inhibitors of the PD-1/PD-L1 interaction.
• Small peptides like FJ15596 represent a promising therapeutic modality for cancer immunotherapy with potential for improved tumor penetration.
• This approach is applicable to the development of peptide scaffolds for targeting other therapeutically relevant protein-protein interactions.