Journal
ACS CHEMICAL BIOLOGY
Volume 9, Issue 1, Pages 247-257Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cb400740c
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Funding
- Cystic Fibrosis Canada
- Canadian Institutes of Health Research (CIHR)
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Bertram Hoffmeister Child & Family Research Institute (CFRI) Postdoctoral Award
- Clinical Research Scholar Award from the Michael Smith Foundation for Health Research
- Aubrey J. Tingle Professorship in Pediatric Immunology
- Canadian Institutes of Health Research [CIHR MOP-57830]
- National Institutes of Health [1R01HG005084-01A1, 1R01GM104975-01]
- National Science Foundation [DBI 0953881]
- CIFAR Genetic Networks Program
- Direct For Biological Sciences [0953881] Funding Source: National Science Foundation
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R01HG005084] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM104975] Funding Source: NIH RePORTER
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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.
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