Unbiased screening of marine sponge extracts for antiinflammatory agents combined with chemical genomics identifies girolline as an inhibitor of protein synthesis

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

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

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 highthroughput 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.

Original languageEnglish (US)
Pages (from-to)247-257
Number of pages11
JournalACS Chemical Biology
Volume9
Issue number1
DOIs
StatePublished - Jan 17 2014

Bibliographical note

Funding Information:
This work was financially supported by Cystic Fibrosis Canada (SET), the Canadian Institutes of Health Research (CIHR: SET), and the Natural Sciences and Engineering Research Council of Canada (NSERC: R.J.A. and S.E.T.). S.-Y.F. was supported by Bertram Hoffmeister Child & Family Research Institute (CFRI) Postdoctoral Award. S.E.T. was supported by a Clinical Research Scholar Award from the Michael Smith Foundation for Health Research and the Aubrey J. Tingle Professorship in Pediatric Immunology. J.S.P., S.C.L., and C.B. were supported by the Canadian Institutes of Health Research (CIHR MOP-57830). C.L.M. and R.D. are partially supported by grants from the National Institutes of Health (1R01HG005084-01A1, 1R01GM104975-01) and a grant from the National Science Foundation (DBI 0953881). C.L.M. and C.B. are also supported by the CIFAR Genetic Networks Program. The authors would like to thank L. Sly, A. Tang, N. Marr, H. Yang, J. Wang, K. Hsu, S. Wang, and T. Wang for their technical assistance and guidance with this project.

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