Blocking of the PD-1/PD-L1 Interaction by a D -Peptide Antagonist for Cancer Immunotherapy

Abstract

Blockade of the protein-protein interaction between the transmembrane protein programmed cell death protein1 (PD-1) and its ligand PD-L1 has emerged as a promising immunotherapy for treating cancers. Using the technology of mirror-image phage display, we developed the first hydrolysis-resistant D-peptide antagonists to target the PD-1/PD-L1 pathway. The optimized compound D PPA-1 could bind PD-L1 at an affinity of 0.51μM invitro. A blockade assay at the cellular level and tumor-bearing mice experiments indicated that D PPA-1 could also effectively disrupt the PD-1/PD-L1 interaction invivo. Thus D-peptide antagonists may provide novel low-molecular-weight drug candidates for cancer immunotherapy. Protein chemical synthesis and mirror-image phage display were combined to develop a proteolysis-resistant D-peptide antagonist ( D PPA-1) which targets the immune checkpoint protein PD-L1 (the ligand for PD-1, the programmed cell death protein 1). D PPA-1 was found to inhibit the PD-1/PD-L1 protein-protein interaction at the cellular level. IgV=immunoglobulin-like variable.