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Small-Molecule TLR8 Antagonists via Structure-Based Rational Design
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DOI：10.1016/j.chembiol.2018.07.004.png)
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Abstract
En 中文
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 similar to picomolar IC50 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.
Keywords:
TOLL-LIKE RECEPTORS
ACTIVATE B-CELLS
NF-KAPPA-B
IMMUNE-RESPONSE
CUTTING EDGE
STRANDED-RNA
RECOGNITION
TOLL-LIKE-RECEPTOR-7
INHIBITION
EXPRESSION
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