Targeting toll-like receptor 7 as a therapeutic development strategy for systemic lupus erythematosus  

作　　者：Meng Wang Hekai Chen Tuan Zhang Zhikuan Zhang Xuwen Xiang Meng Gao Yilan Guo Shuangshuang Jiang Kejun Yin Mintao Chen Jian Huang Xincheng Zhong Umeharu Ohto Jing Li Toshiyuki Shimizu Hang Yin 

机构地区：[1]State Key Laboratory of Membrane Biology,School of Pharmaceutical Sciences,Tsinghua-Peking Center for Life Sciences,Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology(Ministry of Education),Tsinghua University,Beijing 100084,China [2]Graduate School of Pharmaceutical Sciences,the University of Tokyo,Tokyo 113-0033,Japan [3]Department of Rheumatology and Clinical Immunology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences,Peking Union Medical College,Beijing 100032,China [4]Toll Biotech Co.,Ltd.(Beijing),Beijing 102209,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第11期4899-4913,共15页药学学报（英文版）

基　　金：National Natural Science Foundation of China(Grant No.22137004 and 82430109);Beijing Outstanding Young Scientist Program Grant No.BJJWZYJH01201910003013(China);Natural Science Foundation of Beijing,China(Grant No.IS23107).

摘　　要：Endosomal TLRs(TLR3/7/8/9)are highly analogous innate immunity sensors for various viral or bacterial RNA/DNA molecular patterns.Among them,TLR7,in particular,has been suggested to be a target for various inflammatory disorders and autoimmune diseases including systemic lupus erythematosus(SLE);but few small-molecule inhibitors with elaborated mechanism have been reported in literature.Here,we reported a well-characterized human TLR7-specific small-molecule inhibitor,TH-407b,with promising potency and negligible cytotoxicity through a novel binding mechanism.Notably,TH-407b not only effectively inhibited TLR7-mediated pro-inflammatory signaling in a variety of cultured cell lines but also demonstrated potent inflammation suppressing activities in primary peripheral blood mononuclear cells(PBMCs)derived from SLE patients.Furthermore,TH-407b showed prominent efficacy in vivo,improved survival rate and ameliorated symptoms of SLE model mice.To obtain molecular insights into the TH-407b derivatives’inhibition mechanism,we performed the structural analysis of TLR7/TH-407b complex using cryogenic electron microscopy(cryo-EM)method.As an atomistic resolution cryo-EM structure of the TLR family,it not only of value to facilitate structure-based drug design,but also shed light to methodology development of small proteins using EM.Significantly,TH-407b has unveiled an inhibition strategy for TLR7 via stabilizing its resting/inactivated state.Such a resting state could be generally applicable to all TLRs,rendering a useful method for targeting this group of important immunological receptors.

关 键 词：TLR7 Small-moleculeinhibitor Atomisticresolutioncryo-EM structure Resting state Systemiclupus erythematosus MRL 

分 类 号：R593.24[医药卫生—内科学]