Small-Molecule TLR8 Antagonists via Structure-Based Rational Design
| Autor: | Umeharu Ohto, Toshiyuki Shimizu, Kyoin Koo, Kentaro Sakaniwa, H. Tanji, Zhenyi Hu, Shuangshuang Jiang, Hang Yin, Albert Candia, Shuting Zhang, Jean Chan |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Clinical Biochemistry Chemical biology Computational biology Biology medicine.disease_cause Crystallography X-Ray Biochemistry Peripheral blood mononuclear cell Article Protein–protein interaction Autoimmunity Autoimmune Diseases Small Molecule Libraries 03 medical and health sciences Mice 0302 clinical medicine Drug Discovery medicine Animals Humans Receptor Molecular Biology Cells Cultured Pharmacology Binding Sites Rational design TLR8 Small molecule Molecular Docking Simulation 030104 developmental biology HEK293 Cells Toll-Like Receptor 8 030220 oncology & carcinogenesis Drug Design Molecular Medicine Computer-Aided Design |
| Zdroj: | Cell chemical biology. 25(10) |
| ISSN: | 2451-9448 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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