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首页> 外文学位 >Inhibition of TLR2 Signaling by Small Molecule Inhibitors Targeting a Pocket Within the TLR2 TIR Domain.
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Inhibition of TLR2 Signaling by Small Molecule Inhibitors Targeting a Pocket Within the TLR2 TIR Domain.

机译：针对小分子抑制剂的TLR2 TIR域内的小分子对TLR2信号的抑制。

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摘要

Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll-Interleukin-1 receptor resistance (TIR) domains. For all TLRs, except TLR3, recruitment of the adapter, MyD88, to the TIR domains results in downstream signaling that culminates in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate diseases caused by TLR-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein-protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a "pocket" adjacent to the highly conserved P681 and G682 residues of the BB loop. Using "Computer-Aided Drug Design" (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this "BB loop pocket" and, potentially, disrupt TLR2 signaling. In silico screening identified 149 lead compounds and 20 FDA-approved drugs based on their predicted ability to bind in the BB loop pocket. These were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. In this screen, C 16H15NO4 ("C29") was identified as a potential TLR2 inhibitor. C29, and a derivative, ortho-vanillin ( o-vanillin), inhibited TLR2/1 and TLR2/6 signaling in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages induced by synthetic and bacterial TLR2 agonists. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6 signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle for this novel CADD approach for the identification of inhibitors of TLR signaling.
机译：Toll样受体（TLR）信号是由细胞内Toll-白介素1受体抗性（TIR）域的二聚化引发的。对于除TLR3以外的所有TLR，将接头MyD88募集到TIR结构域会导致下游信号传导，最终导致促炎性细胞因子的产生。因此，阻断TLR TIR二聚化可改善由TLR介导的高炎症状态引起的疾病。 TLR TIR域内的BB环对于介导某些蛋白质间相互作用至关重要。对人类TLR2 TIR结构域晶体结构的检查显示出一个“口袋”，与BB环的高度保守的P681和G682残基相邻。我们使用“计算机辅助药物设计”（CADD），试图确定一种适合该“ BB环口袋”并可能破坏TLR2信号传导的小分子抑制剂。在计算机筛选中，根据预测的结合在BB环口袋中的能力，鉴定出149种主要化合物和20种FDA批准的药物。在HEK293T-TLR2转染子中筛选了抑制TLR2介导的IL-8 mRNA的能力。在该筛选中，C 16H15NO4（“ C29”）被鉴定为潜在的TLR2抑制剂。 C29及其衍生物邻香兰素（邻香兰素）抑制人HEK-TLR2和THP-1细胞中的TLR2 / 1和TLR2 / 6信号传导，但在合成和细菌TLR2诱导的鼠巨噬细胞中仅抑制TLR2 / 1信号传导。激动剂。 BB环口袋残基的诱变揭示了TLR2 / 1的必不可少的作用，但TLR2 / 6信号却没有，暗示了不同的作用。用邻香兰素治疗的小鼠表现出减少的TLR2诱导的炎症。我们的数据为这种新颖的CADD方法鉴定TLR信号抑制剂提供了原理证明。

著录项

  • 作者

    Mistry, Pragnesh Dilipkumar.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Immunology.;Molecular biology.;Cellular biology.;Oncology.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 159 p.
  • 总页数 159
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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