6TY5

Crystal structure of human TLR8 in complex with Compound 11

Summary for 6TY5

• Entry DOI: 10.2210/pdb6ty5/pdb
• Descriptor: Toll-like receptor 8, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: rna recognition leucine rich repeats glycosylation structure based drug design immune system innate immunity, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 192811.25

Authors

Faller, M.,Zink, F. (deposition date: 2020-01-15, release date: 2020-08-12, Last modification date: 2024-01-24)

Primary citation

Knoepfel, T.,Nimsgern, P.,Jacquier, S.,Bourrel, M.,Vangrevelinghe, E.,Glatthar, R.,Behnke, D.,Alper, P.B.,Michellys, P.Y.,Deane, J.,Junt, T.,Zipfel, G.,Limonta, S.,Hawtin, S.,Andre, C.,Boulay, T.,Loetscher, P.,Faller, M.,Blank, J.,Feifel, R.,Betschart, C.
Target-Based Identification and Optimization of 5-Indazol-5-yl Pyridones as Toll-like Receptor 7 and 8 Antagonists Using a Biochemical TLR8 Antagonist Competition Assay.
J.Med.Chem., 63:8276-8295, 2020

PubMed Abstract: Inappropriate activation of endosomal TLR7 and TLR8 occurs in several autoimmune diseases, in particular systemic lupus erythematosus (SLE). Herein, the development of a TLR8 antagonist competition assay and its application for hit generation of dual TLR7/8 antagonists are reported. The structure-guided optimization of the pyridone hit using this biochemical assay in combination with cellular and TLR8 cocrystal structural data resulted in the identification of a highly potent and selective TLR7/8 antagonist () with efficacy. The two key steps for optimization were (i) a core morph guided by a TLR7 sequence alignment to achieve a dual TLR7/8 antagonism profile and (ii) introduction of a fluorine in the piperidine ring to reduce its basicity, resulting in attractive oral pharmacokinetic (PK) properties and improved TLR8 binding affinity.

PubMed: 32786235
DOI: 10.1021/acs.jmedchem.0c00130

Experimental method

X-RAY DIFFRACTION (2.793 Å)