Rationally Designed Small-Molecule Inhibitors Targeting an Unconventional Pocket on the TLR8 Protein-Protein Interface
Rationally Designed Small-Molecule Inhibitors Targeting an Unconventional Pocket on the TLR8 Protein-Protein Interface
复制标题
针对 TLR8 蛋白质-蛋白质界面上非常规口袋的合理设计的小分子抑制剂
DOI：
10.1021/acs.jmedchem.9b02128
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发表时间：
2020-04-23
影响因子：
7.3
通讯作者：
Yin, Hang
中科院分区：
文献类型：
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作者：
Jiang, Shuangshuang;Tanji, Hiromi;Yin, Hang
针对蛋白质-蛋白质界面的小分子抑制剂的合理设计收效甚微。在这里，我们设计了一系列具有新型支架的三氮唑类化合物，以特异性地干预TLR8异构化的相互作用。在多项检测中，TH1027被确定为TLR8的高效和特异的抑制剂。成功地解决了TLR8与TH1027络合物的X射线晶体结构，从机理上深入了解了TLR8的结合模式，证实了TH1027位于两个TLR8单体之间，被认为是一个非常规的口袋，从而阻止了TLR8的激活。进一步的生物学评估显示，TH1027呈剂量依赖性地抑制人类单核细胞系、外周血单核细胞和类风湿性关节炎患者标本中TLR8介导的炎症反应，表明TH1027对自身免疫性疾病具有强大的治疗潜力。
Rational designs of small-molecule inhibitors targeting protein-protein interfaces have met little success. Herein, we have designed a series of triazole derivatives with a novel scaffold to specifically intervene with the interaction of TLR8 homomerization. In multiple assays, TH1027 was identified as a highly potent and specific inhibitor of TLR8. A successful solution of the X-ray crystal structure of TLR8 in complex with TH1027 provided an in-depth mechanistic insight into its binding mode, validating that TH1027 was located between two TLR8 monomers and recognized as an unconventional pocket, thereby preventing TLR8 from activation. Further biological evaluations showed that TH1027 dose-dependently suppressed the TLR8-mediated inflammatory responses in both human monocyte cell lines, peripheral blood mononuclear cells, and rheumatoid arthritis patient specimens, suggesting a strong therapeutic potential against autoimmune diseases.