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

Small-Molecule TLR8 Antagonists via Structure-Based Rational Design.

Author information

1
Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80309, USA; School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100082, China.
2
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
3
School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100082, China.
4
Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80309, USA.
5
Dynavax Technologies Corporation, Berkeley, CA 94710, USA.
6
Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80309, USA; School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100082, China. Electronic address: yin_hang@tsinghua.edu.cn.

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

PMID:
30100350
PMCID:
PMC6195466
[Available on 2019-10-18]
DOI:
10.1016/j.chembiol.2018.07.004
[Indexed for MEDLINE]
Free PMC Article

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