Small-Molecule TLR8 Antagonists via Structure-Based Rational Design

Cell Chem Biol. 2018 Oct 18;25(10):1286-1291.e3. doi: 10.1016/j.chembiol.2018.07.004. Epub 2018 Aug 9.

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 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: TLR8; antagonists; autoimmunity; protein-protein interactions; rational design.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases / drug therapy
  • Binding Sites
  • Cells, Cultured
  • Computer-Aided Design
  • Crystallography, X-Ray
  • Drug Design
  • HEK293 Cells
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*
  • Toll-Like Receptor 8 / antagonists & inhibitors*
  • Toll-Like Receptor 8 / chemistry
  • Toll-Like Receptor 8 / metabolism

Substances

  • Small Molecule Libraries
  • TLR8 protein, human
  • Toll-Like Receptor 8