Unbiased Screening of Marine Sponge Extracts for Antiinflammatory Agents Combined with Chemical Genomics Identifies Girolline as an Inhibitor of Protein Synthesis

作者：Fung Shan Yu; Sofiyev Vladimir; Schneiderman Julia; Hirschfeld Aaron F; Victor Rachel E; Woods Kate; Piotrowski Jeff S; Deshpande Raamesh; Li Sheena C; de Voogd Nicole J; Myers Chad L; Boone Charlie; Andersen Raymond J; Turvey Stuart E^*

来源：ACS Chemical Biology, 2014, 9(1): 247-257.

DOI：10.1021/cb400740c

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.

• 出版日期2014-1