Light-Activated Azobenzene Peptide Inhibitor of the PD-1/PD-L1 Interaction

Inhibiting the protein-protein interaction between programmed cell death 1 (PD-1) and its ligand programmed cell death ligand 1 (PD-L1) has become a focal point in immunotherapy for cancer treatments. Limitations of antibody treatments remain prevalent leaving an urgent need for alternative inhibitors of PD-1/PD-L1. Utilizing the photo-switching ability of the well studied azobenzenes, we developed a photo-controlled PD-1/PD-L1 peptide inhibitor. The azobenzene peptide selectively inhibits the PD-1/PD-L1 interaction when in the cis isomer, while showing no appreciable inhibition in the trans isomer. The light-activated inhibitor demonstrated improved activity compared to the canonical peptide it was derived from in a luminescent cell-based PD-1/PD-L1 blockade assay. The light-activated peptide demonstrates the applicatbilty of photoisomerization for mimicking β-hairpin motifs in PD-1/PD-L1 inhibition.