RESUMO
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.
Assuntos
Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Imidazóis/isolamento & purificação , Imidazóis/farmacologia , Poríferos/química , Biossíntese de Proteínas/efeitos dos fármacos , Animais , Células CHO , Células Cultivadas , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Humanos , Interleucina-6/imunologia , Interleucina-8/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Receptores Toll-Like/imunologiaRESUMO
Two highly modified linear tetrapeptides, padanamides A (1) and B (2), are produced by laboratory cultures of a Streptomyces sp. obtained from a marine sediment. Padanamide B is cytotoxic to Jurkat cells, and a chemical genomics analysis using Saccharomyces cerevisiae deletion mutants suggested that padanamide A inhibits cysteine and methionine biosynthesis or that these amino acids are involved in the yeast's response to the peptide.