Small-Molecule TLR8 Antagonists via Structure-Based Rational Design

Abstract

Rational design of drug-like small-molecule ligands based on structural information of proteins remains a significant challenge in chemical biology. In particular, designs targeting protein-protein interfaces have met little success given the dynamic nature of the protein surfaces. Herein, we utilized the structure of a small-molecule ligand in complex with Toll-like receptor 8 (TLR8) as a model system due to TLR8's clinical relevance. Overactivation of TLR8 has been suggested to play a prominent role in the pathogenesis of various autoimmune diseases; however, there are still few small-molecule antagonists available, and our rational designs led to the discovery of six exceptionally potent compounds with ∼picomolar IC values. Two X-ray crystallographic structures validated the contacts within the binding pocket. A variety of biological evaluations in cultured cell lines, human peripheral blood mononuclear cells, and splenocytes from human TLR8-transgenic mice further demonstrated these TLR8 inhibitors' high efficacy, suggesting strong therapeutic potential against autoimmune disorders.

Sensing of HIV-1 by TLR8 activates human T cells and reverses latency

“…2b). To further assess the specificity of the TLR8 response, we utilized TLR8 inhibitors that stabilize the TLR8 dimer in its inactive state 45,46 . CD4+ T cells were pre-treated with the structurally optimized TLR8 inhibitors CU-CPT9a and CU-CPT9b, or the negative control compound CU-CPT6, for 2 h prior to TCR activation and stimulation with CL264, CL75, pU/ pLA or the TLR2 ligand FSL-1 for 24 h. TLR8-induced IL-6 was significantly reduced by inhibitors CU-CPT9a and CU-CPT9b ( Fig.…”

RNA is taking its Toll: Impact of RNA‐specific Toll‐like receptors on health and disease

“…This knowledge recently led to the development of new TLR8 antagonists, the CU‐CPT 9 derivates, which stabilize the receptor's resting state to inhibit its activation . The antagonists possess IC50 values in a nM‐pM range and exhibit high specificity with the ability to discriminate between TLR7 and TLR8 which is superior compared to previous inhibitors . This new class of antagonists can hopefully be transferred to other TLRs and may lead to enhanced treatment options for patients suffering from autoimmune diseases such as SLE or RA.…”

Targeting the innate immune receptor TLR8 using small-molecule agents

“…Intensive in vitro structural and biophysical analyses of TLR8 have been conducted. To date, agonist-induced activated dimer structures, an unliganded dimer structure and antagonist-induced dimer structures have already been reported, and functional mechanisms have been proposed (Tanji et al, 2013(Tanji et al, , 2015Zhang, Hu et al, 2018;Hu et al, 2018). Here, we summarize recent structural studies and discuss the mechanism by which ligand binding influences or regulates the activity of TLR8.…”