Endosomal TLRs (TLR3/7/8/9) are highly analogous innate immunity sensors for various viral or bacterial RNA/DNA mol. 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-mol. inhibitors with elaborated mechanism have been reported in literature.Here, we reported a well-characterized human TLR7-specific small-mol. 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 mol. insights into the TH-407b derivatives′ inhibition mechanism, we performed the structural anal. 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 methodol. 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 immunol. receptors.