8PFI

Crystal structure of human TLR8 in complex with compound 34

Summary for 8PFI

• Entry DOI: 10.2210/pdb8pfi/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: tlr8, toll-like receptor, immune, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 193151.76

Authors

Faller, M.,Zink, F. (deposition date: 2023-06-16, release date: 2023-08-16, Last modification date: 2024-10-16)

Primary citation

Alper, P.,Betschart, C.,Andre, C.,Boulay, T.,Cheng, D.,Deane, J.,Faller, M.,Feifel, R.,Glatthar, R.,Han, D.,Hemmig, R.,Jiang, T.,Knoepfel, T.,Maginnis, J.,Mutnick, D.,Pei, W.,Ruzzante, G.,Syka, P.,Zhang, G.,Zhang, Y.,Zink, F.,Zipfel, G.,Hawtin, S.,Junt, T.,Michellys, P.Y.
Discovery of the TLR7/8 Antagonist MHV370 for Treatment of Systemic Autoimmune Diseases.
Acs Med.Chem.Lett., 14:1054-1062, 2023

PubMed Abstract: Toll-like receptor (TLR) 7 and TLR8 are endosomal sensors of the innate immune system that are activated by GU-rich single stranded RNA (ssRNA). Multiple genetic and functional lines of evidence link chronic activation of TLR7/8 to the pathogenesis of systemic autoimmune diseases (sAID) such as Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE). This makes targeting TLR7/8-induced inflammation with small-molecule inhibitors an attractive approach for the treatment of patients suffering from systemic autoimmune diseases. Here, we describe how structure-based optimization of compound resulted in the discovery of (MHV370, ()-N-(4-((5-(1,6-dimethyl-1-pyrazolo[3,4-]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1-pyrazolo[4,3-]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide). Its activity allows for further profiling toward clinical trials in patients with autoimmune disorders, and a Phase 2 proof of concept study of MHV370 has been initiated, testing its safety and efficacy in patients with Sjögren's syndrome and mixed connective tissue disease.

PubMed: 37583811
DOI: 10.1021/acsmedchemlett.3c00136

Experimental method

X-RAY DIFFRACTION (2.785 Å)