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

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

扫码查看
原文链接
  • 万方数据
  • 维普
Endosomal TLRs(TLR3/7/8/9)are highly analogous innate immunity sensors for various viral or bacterial RNA/DNA molecular pattems.Among them,TLR7,in particular,has been suggested to be a target for various inflammatory disorders and autoimmune diseases including systemic lupus er-ythematosus(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 molec-ular 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 reso-lution 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.

TLR7Small-molecule inhibitorAtomistic resolution cryo-EM structureResting stateSystemic lupus erythematosusMRLSelectiveCytokine

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

展开 >

Toll Biotech Co.,Ltd.(Beijing),Beijing 102209,China

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

Graduate School of Pharmaceutical Sciences,the University of Tokyo,Tokyo 113-0033,Japan

Institute of Bio-Architecture and Bio-Interactions(IBABI),Shenzhen Medical Academy of Research and Translation,Shenzhen 518107,China

Department of Rheumatology and Clinical Immunology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences,Peking Union Medical College,Beijing 100032,China

展开 >

2024

10.1016/j.apsb.2024.08.016

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(11)