Blockade of the protein-protein interaction between the transmembrane protein programmed cell death protein 1 (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 0.51 μM in vitro. 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 in vivo. Thus D-peptide antagonists may provide novel low-molecular-weight drug candidates for cancer immunotherapy.

Blockade of the protein-protein interaction between the transmembrane protein programmed cell death protein 1 (PD-1) and its ligand PD-L1 has emerged as ap romising immunotherapyf or treating cancers.U sing the technology of mirror-image phage display,wedeveloped the first hydrolysisresistant d-peptide antagonists to target the PD-1/PD-L1 pathway.T he optimizedc ompound D PPA-1 could bind PD-L1 at an affinity of 0.51 mm in vitro.Ablockade assaya tt he cellular level and tumor-bearing mice experiments indicated that D PPA-1 could also effectively disrupt the PD-1/PD-L1 interaction in vivo.T hus d-peptide antagonists may provide novel low-molecular-weight drug candidates for cancer immunotherapy.Scheme 1. A) The PD-1/PD-L1 interaction mediates cancer immune escape. B) d-Peptide antagonists targeting PD-L1 can inhibit the PD-1/ PD-L1 interaction for cancer immunotherapy.

No abstract

No abstract