Therapeutic inhibition of pro-inflammatory signaling and toxicity to staphylococcal enterotoxin B by a synthetic dimeric BB-loop mimetic of MyD88.
Therapeutic inhibition of pro-inflammatory signaling and toxicity to staphylococcal enterotoxin B by a synthetic dimeric BB-loop mimetic of MyD88.
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DOI：
10.1371/journal.pone.0040773
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Saikh KU
中科院分区：
文献类型：
--
作者：
Kissner TL;Ruthel G;Alam S;Mann E;Ajami D;Rebek M;Larkin E;Fernandez S;Ulrich RG;Ping S;Waugh DS;Rebek J Jr;Saikh KU
Staphylococcal enterotoxin B (SEB) exposure triggers an exaggerated pro-inflammatory cytokine response that often leads to toxic shock syndrome (TSS) associated with organ failure and death. MyD88 mediates pro-inflammatory cytokine signaling induced by SEB exposure and MyD88−/− mice are resistant to SEB intoxication, suggesting that MyD88 may be a potential target for therapeutic intervention. We targeted the BB loop region of the Toll/IL-1 receptor (TIR) domain of MyD88 to develop small-molecule therapeutics. Here, we report that a synthetic compound (EM-163), mimic to dimeric form of BB-loop of MyD88 attenuated tumor necrosis factor (TNF)- α, interferon (IFN)-γ, interleukin (IL)-1β, IL-2 and IL-6 production in human primary cells, whether administered pre- or post-SEB exposure. Results from a direct binding assay, and from MyD88 co-transfection/co-immunoprecipitation experiments, suggest that EM-163 inhibits TIR-TIR domain interaction. Additional results indicate that EM-163 prevents MyD88 from mediating downstream signaling. In an NF-kB-driven reporter assay of lipopolysaccharide-stimulated MyD88 signaling, EM-163 demonstrated a dose-dependent inhibition of reporter activity as well as TNF-α and IL-1β production. Importantly, administration of EM-163 pre- or post exposure to a lethal dose of SEB abrogated pro-inflammatory cytokine responses and protected mice from toxic shock-induced death. Taken together, our results suggest that EM-163 exhibits a potential for therapeutic use against SEB intoxication.
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影响因子：
3.7
作者：
Frei R;Steinle J;Birchler T;Loeliger S;Roduit C;Steinhoff D;Seibl R;Büchner K;Seger R;Reith W;Lauener RP
通讯作者：
Lauener RP
DOI：
10.1073/pnas.0510802103
发表时间：
2006-02-21
影响因子：
11.1
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影响因子：
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影响因子：
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影响因子：
4.8
作者：
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通讯作者：
Pascual, Jaime