What question did this study set out to answer?

To identify small molecule inhibitors targeting the BB loop pocket of the human TLR2 TIR domain to selectively interrupt TLR2 signaling and suppress hyperinflammation.

April 13, 2015Proceedings of the National Academy of SciencesOpen Access

Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain

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Authors

PMPragnesh MistryNational Institute of Arthritis and Musculoskeletal and Skin Diseases MLMichelle LairdBipar RSRyan S. SchwarzFort Lewis College

Discussion

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Implication

Preclinical study demonstrates targeted small molecule inhibition of TLR2 signaling in human cells and mice, indicating a viable strategy to ameliorate TLR2-mediated hyperinflammatory states.

Key Points

To identify small molecule inhibitors targeting the BB loop pocket of the human TLR2 TIR domain to selectively interrupt TLR2 signaling and suppress hyperinflammation.
In silico computer-aided drug design screened 149 candidate molecules and 20 FDA-approved drugs for docking into the pocket adjacent to P681 and G682 residues of the human TLR2 TIR domain crystal structure.
Identified compounds were evaluated for inhibition of TLR2-driven IL-8 mRNA in HEK293T-TLR2 transfectants, followed by validation in THP-1 human cells and murine macrophages.
Mutagenesis of BB loop pocket residues was conducted alongside in vivo testing of the active derivative ortho-vanillin in TLR2 agonist-challenged mice.
Compound C29 and its derivative ortho-vanillin selectively blocked synthetic and bacterial agonist-induced TLR2/1 and TLR2/6 signaling in human cells, while failing to inhibit other TLR pathways or TNF-α.
BB loop pocket mutagenesis established that these residues are essential for TLR2/1 signaling but dispensable for TLR2/6 signaling.
Mice treated with ortho-vanillin showed a marked reduction in TLR2-induced inflammation compared to controls.

Cite This Study

Mistry et al. (2015) studied this question.

synapsesocial.com/papers/6aa8ded5022accd6d12c7e82 https://doi.org/10.1073/pnas.1422576112

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April 13, 2015Proceedings of the National Academy of SciencesOpen Access

Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain

View Full Paper

Ask AI

Bookmark

Authors

PMPragnesh MistryNational Institute of Arthritis and Musculoskeletal and Skin Diseases MLMichelle LairdBipar RSRyan S. SchwarzFort Lewis College

Discussion

Member takes

Implication

Preclinical study demonstrates targeted small molecule inhibition of TLR2 signaling in human cells and mice, indicating a viable strategy to ameliorate TLR2-mediated hyperinflammatory states.

Key Points

To identify small molecule inhibitors targeting the BB loop pocket of the human TLR2 TIR domain to selectively interrupt TLR2 signaling and suppress hyperinflammation.
In silico computer-aided drug design screened 149 candidate molecules and 20 FDA-approved drugs for docking into the pocket adjacent to P681 and G682 residues of the human TLR2 TIR domain crystal structure.
Identified compounds were evaluated for inhibition of TLR2-driven IL-8 mRNA in HEK293T-TLR2 transfectants, followed by validation in THP-1 human cells and murine macrophages.
Mutagenesis of BB loop pocket residues was conducted alongside in vivo testing of the active derivative ortho-vanillin in TLR2 agonist-challenged mice.
Compound C29 and its derivative ortho-vanillin selectively blocked synthetic and bacterial agonist-induced TLR2/1 and TLR2/6 signaling in human cells, while failing to inhibit other TLR pathways or TNF-α.
BB loop pocket mutagenesis established that these residues are essential for TLR2/1 signaling but dispensable for TLR2/6 signaling.
Mice treated with ortho-vanillin showed a marked reduction in TLR2-induced inflammation compared to controls.

Cite This Study

Mistry et al. (2015) studied this question.

synapsesocial.com/papers/6aa8ded5022accd6d12c7e82 https://doi.org/10.1073/pnas.1422576112

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