Structure based design and synthesis of novel Toll-like Receptor 2 (TLR 2) lipid antagonists

Bioorg Med Chem Lett. 2021 May 15:40:127861. doi: 10.1016/j.bmcl.2021.127861. Epub 2021 Feb 23.

Abstract

Toll-like receptors (TLRs) play key role in innate immune response to Damage Associated Molecular Patterns (DAMPs) and Pathogen Associated Molecular Patterns (PAMPs). DAMP/PAMP-mediated activation of TLRs triggers NFκB signaling resulting in pro-inflammatory cytokine release. Using TLR2-Pam2CSK4 agonist co-crystal structure information, we designed and synthesized a novel series of Toll-like Receptor 2 (TLR2) lipid antagonists and identified compounds 14, 15 and 17 with sub-micromolar potency. TLR2 antagonists that we identified are stable for > 1.0 h in both gastric juice and PBS buffer and could be used as research tools.

Keywords: Bacterial infections; IL8 inhibition; Neurodegeneration; Structure-based drug discovery; TLR inhibitor; TLR2.

MeSH terms

  • Crystallization
  • Cytokines / metabolism
  • Drug Discovery
  • Humans
  • Lipids / chemistry*
  • NF-kappa B / metabolism
  • Oligopeptides / chemistry*
  • Protein Binding
  • Signal Transduction
  • Structure-Activity Relationship
  • Toll-Like Receptor 2 / agonists*
  • Toll-Like Receptor 2 / antagonists & inhibitors*
  • Toll-Like Receptor 2 / chemistry
  • Toll-Like Receptor 9 / agonists*
  • Toll-Like Receptor 9 / chemistry

Substances

  • Cytokines
  • Lipids
  • NF-kappa B
  • Oligopeptides
  • Toll-Like Receptor 2
  • Toll-Like Receptor 9
  • PAM2-CSK4