化学
小分子
组合化学
接口(物质)
分子
生物物理学
纳米技术
生物化学
生物
有机化学
吉布斯等温线
材料科学
作者
Shuangshuang Jiang,Hiromi Tanji,Kejun Yin,Shuting Zhang,Kentaro Sakaniwa,Jian Huang,Yi Yang,Jing Li,Umeharu Ohto,Toshiyuki Shimizu,Hang Yin
标识
DOI:10.1021/acs.jmedchem.9b02128
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI