Macrocyclic Peptide Inhibitor of PD-1/PD-L1 Immune Checkpoint

Immune checkpoint-targeting antibodies brought a recent breakthrough in cancer immunotherapy, but the development of small molecule checkpoint inhibitors is lagging behind. Here, the characterization of a macrocyclic peptide (p101) capable of blocking the PD-L1/PD-1 immune checkpoint is reported at the interface of cancer and immune cells. NMR and other physicochemical data demonstrate that the macrocycle binds to PD-L1 to sterically hinder its interaction with PD-1. The crystal structure of the complex highlights the detailed features of the binding site and demonstrates that the interaction is primarily guided by hydrophobic forces. A reporter PD-L1/PD-1 blockade bioassay demonstrates that p101 is able to inhibit the interaction in the cellular environment. Finally, it is shown that p101 releases the immune response of primary human T-cells from PD-L1 mediated inhibition.

Automated summary

The study reports a macrocyclic peptide p101 capable of blocking the PD-L1/PD-1 immune checkpoint, showing that the interaction is primarily guided by hydrophobic forces. Experimental results demonstrate that p101 can effectively inhibit the interaction between PD-L1 and PD-1 in the cellular environment, releasing the immune response of human T cells.