3 years ago

Bioactive Macrocyclic Inhibitors of the PD-1/PD-L1 Immune Checkpoint

Bioactive Macrocyclic Inhibitors of the PD-1/PD-L1 Immune Checkpoint
Tryfon Zarganes-Tzitzikas, Przemyslaw Grudnik, Katarzyna Magiera-Mularz, Justyna Kocik, Lukasz Skalniak, Tad A. Holak, Alexander Dömling, Ewa Rudzinska-Szostak, Grzegorz Dubin, Shabnam Shaabani, Bogdan Musielak, Krzysztof M. Zak, Dominik Sala, Łukasz Berlicki
Blockade of the immunoinhibitory PD-1/PD-L1 pathway using monoclonal antibodies has shown impressive results with durable clinical antitumor responses. Anti-PD-1 and anti-PD-L1 antibodies have now been approved for the treatment of a number of tumor types, whereas the development of small molecules targeting immune checkpoints lags far behind. We characterized two classes of macrocyclic-peptide inhibitors directed at the PD-1/PD-L1 pathway. We show that these macrocyclic compounds act by directly binding to PD-L1 and that they are capable of antagonizing PD-L1 signaling and, similarly to antibodies, can restore the function of T-cells. We also provide the crystal structures of two of these small-molecule inhibitors bound to PD-L1. The structures provide a rationale for the checkpoint inhibition by these small molecules, and a description of their small molecule/PD-L1 interfaces provides a blueprint for the design of small-molecule inhibitors of the PD-1/PD-L1 pathway. Circle of life: Macrocyclic peptide inhibitors can block the PD-1/PD-L1 pathway by directly binding to PD-L1 and, similarly to anti-PD-L1 antibodies, they can restore the function of T-cells. Structures of the macrocycle/PD-L1 interfaces provide a foundation for the design of small-molecule inhibitors with antitumor properties.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/anie.201707707

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