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Unbiased Screening of Marine Sponge Extracts for Anti-inflammatory Agents Combined with Chemical Genomics Identifies Girolline as an Inhibitor of Protein Synthesis
journal contribution
posted on 2014-01-17, 00:00 authored by 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. TurveyToll-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.