Unbiased Screening of Marine Sponge Extracts for Anti-inflammatory Agents Combined with Chemical Genomics Identifies Girolline as an Inhibitor of Protein Synthesis
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- 作者：Shan-Yu Fung ; Vladimir Sofiyev ; Julia Schneiderman ; Aaron F. Hirschfeld ; Rachel E. Victor ; Kate Woods ; Jeff S. Piotrowski ; Raamesh Deshpande ; Sheena C. Li ; Nicole J. de Voogd ; Chad L. Myers ; Charlie Boone ; Raymond J. Andersen ; Stuart E. Turvey
- 刊名：ACS Chemical Biology
- 出版年：2014
- 出版时间：January 17, 2014
- 年：2014
- 卷：9
- 期：1
- 页码：247-257
- 全文大小：699K
- ISSN：1554-8937
文摘
Toll-like receptors (TLRs) play a critical role in innate immunity, but activation of TLR signaling pathways is also associated with many harmful inflammatory diseases. Identification of novel anti-inflammatory molecules targeting TLR signaling pathways is central to the development of new treatment approaches for acute and chronic inflammation. We performed high-throughput screening from crude marine sponge extracts on TLR5 signaling and identified girolline. We demonstrated that girolline inhibits signaling through both MyD88-dependent and -independent TLRs (i.e., TLR2, 3, 4, 5, and 7) and reduces cytokine (IL-6 and IL-8) production in human peripheral blood mononuclear cells and macrophages. Using a chemical genomics approach, we identified Elongation Factor 2 as the molecular target of girolline, which inhibits protein synthesis at the elongation step. Together these data identify the sponge natural product girolline as a potential anti-inflammatory agent acting through inhibition of protein synthesis.