小分子
PD-L1
单克隆抗体
免疫检查点
化学
钯
免疫系统
抗体
封锁
免疫疗法
癌症研究
立体化学
组合化学
生物化学
受体
生物
免疫学
催化作用
作者
Katarzyna Magiera‐Mularz,Łukasz Skalniak,Krzysztof Żak,Bogdan Musielak,Ewa Rudzinska-Szostak,Łukasz Berlicki,Justyna Kocik,P. Grudnik,Dominik Sala,Tryfon Zarganes‐Tzitzikas,Shabnam Shaabani,Alexander Dömlingꝉ,Grzegorz Dubin,Tad A. Holak
标识
DOI:10.1002/anie.201707707
摘要
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.
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