title: Unbiased screening of marine sponge extracts for anti-inflammatory agents combined with chemical genomics identifies girolline as an inhibitor of protein synthesis.
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 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.
authors.affiliation: Department of Pediatrics, British Columbia Children's Hospital and Child & Family Research Institute, University of British Columbia , Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Shan-Yu
authors.initials: SY
authors.lastname: Fung
authors.forename: Vladimir
authors.initials: V
authors.lastname: Sofiyev
authors.forename: Julia
authors.initials: J
authors.lastname: Schneiderman
authors.forename: Aaron F
authors.initials: AF
authors.lastname: Hirschfeld
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Victor
authors.forename: Kate
authors.initials: K
authors.lastname: Woods
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Piotrowski
authors.forename: Raamesh
authors.initials: R
authors.lastname: Deshpande
authors.forename: Sheena C
authors.initials: SC
authors.lastname: Li
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: de Voogd
authors.forename: Chad L
authors.initials: CL
authors.lastname: Myers
authors.forename: Charlie
authors.initials: C
authors.lastname: Boone
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification* / Q000494:pharmacology*; D016466:CHO Cells; D002478:Cells, Cultured; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007093:Imidazoles / Q000302:isolation & purification* / Q000494:pharmacology*; D015850:Interleukin-6 / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D011161:Porifera / Q000737:chemistry*; D014176:Protein Biosynthesis / Q000187:drug effects*; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D007093:Imidazoles; D015850:Interleukin-6; D016209:Interleukin-8; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; C526558:girolline