A Novel Small-Molecule Inhibitor of Endosomal TLRs Reduces Inflammation and Alleviates Autoimmune Disease Symptoms in Murine Models

Cells. 2020 Jul 9;9(7):1648. doi: 10.3390/cells9071648.

Abstract

Toll-like receptors (TLRs) play a fundamental role in the inflammatory response against invading pathogens. However, the dysregulation of TLR-signaling pathways is implicated in several autoimmune/inflammatory diseases. Here, we show that a novel small molecule TLR-inhibitor (TAC5) and its derivatives TAC5-a, TAC5-c, TAC5-d, and TAC5-e predominantly antagonized poly(I:C) (TLR3)-, imiquimod (TLR7)-, TL8-506 (TLR8)-, and CpG-oligodeoxynucleotide (TLR9)-induced signaling pathways. TAC5 and TAC5-a significantly hindered the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), reduced the phosphorylation of mitogen-activated protein kinases, and inhibited the secretion of tumor necrosis factor-α (TNF-α) and interleukin-6. Besides, TAC5-a prevented the progression of psoriasis and systemic lupus erythematosus (SLE) in mice. Interestingly, TAC5 and TAC5-a did not affect Pam3CSK4 (TLR1/2)-, FSL-1 (TLR2/6)-, or lipopolysaccharide (TLR4)-induced TNF-α secretion, indicating their specificity towards endosomal TLRs (TLR3/7/8/9). Collectively, our data suggest that the TAC5 series of compounds are potential candidates for treating autoimmune diseases such as psoriasis or SLE.

Keywords: QSAR; TAC5; Toll-like receptor; antagonist; autoimmune diseases; endosomal TLR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Binding Sites
  • Endosomes / metabolism
  • Female
  • Immunologic Factors / chemistry
  • Immunologic Factors / pharmacology*
  • Immunologic Factors / therapeutic use
  • Interleukin-6 / metabolism
  • Lupus Erythematosus, Systemic / drug therapy*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • NF-kappa B / metabolism
  • Protein Binding
  • Psoriasis / drug therapy*
  • Quantitative Structure-Activity Relationship
  • RAW 264.7 Cells
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Toll-Like Receptors / antagonists & inhibitors*
  • Toll-Like Receptors / chemistry
  • Toll-Like Receptors / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Anti-Inflammatory Agents
  • Immunologic Factors
  • Interleukin-6
  • NF-kappa B
  • Small Molecule Libraries
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha