Fachgebiet Molekulare Biotechnologie & Systembiologie

Natural Products for Drug Discovery

Natural products from plants, microorganisms and animals still play an important role in drug development. A considerable number of small molecules in clinical use, in development or in clinical trials are derived from naturally occurring compounds including antimicrobial and anticancer drugs as well as potent immunosupressants and cholesterol lowering agents. In addition natural products exhibit a wide range of structural diversity with pharmacophores not found in synthetically based screening libraries. Therefore natural products still represent an excellent source for new therapeutics.

The main aims of our research are:

(1) The identification and isolation of bioactive compounds from natural sources, which interfere with the inducible transcription of disease-related genes with particular reference to inflammation, allergy and cancer.

(2) The development of phenotypic assays in cellular models.

(3) Mode-of-action studies of new compounds inhibiting signal transduction pathways in mammalian cells.

(4) Microarrays analyses to estimate the side-effects of potential new drugs, the identification of cellular targets and signal transduction pathways involved in the transcriptional regulation of inflammatory and fibrosis relevant genes.

(5) Target identification and quantification by chemoproteomics through the use of liquid chromatography–tandem mass spectrometry (LC-MS/MS). Target validation through genetic and biochemical means.

Research projects

 

Biochemical and pharmacological evaluation of oxacyclododecindione as lead structure for the development of new anti-inflammatory and anti-fibrotic drugs.

 

  • biological activity of oxacylododecindione:
  •  anti-inflammatory, anti-fibrotic , inhibitor of angiogenesis.
  •   inhibits expression of pro-inflammatory, pro-fibrotic and angiogenesis-related marker genes.
  •  highly potent inhibitor of IL-4/IL-13 (STAT6), IL-6 (STAT3), IFN-γ (STAT1), TGF-β (Smad2/3), NF-κB and Hypoxia (HIF-1α) induced signaling pathways (IC50: 20-40 ng/ml; 68-130 nM).
  • effective in a mouse model of SLE/glomerulonephritis
  • inhibits binding of activated transcription factors to DNA
  •  modulates the expression of miRNAs  
  •  posttranscriptional regulation of gene expression
  •  initial SAR established which allows rational synthesis of derivatives

                                        ⇒   Exact mode(s) of action  still unkown

 

  • Identification of target-proteins by activity based proteome profiling of an alkyne-tagged derivative by click chemistry, drug-pulldown and analysis of enriched proteins by mass spectrometry (LC-MS/MS; Chemoproteomics).

 


Identification and isolation of anti-inflammatory/anti-fibrotic compounds from fungi, plants and cyanobacteria

 Inflammatory and fibrotic diseases are characterized by:

  • abnormal accumulation of inflammatory immune cells (e. g. T-cells, macrophages, neutrophiles, monocytes)
  • complex interplay of immune cells with tissue resident cells (fibroblasts, synovial cells)
  •   over-expression of pro-inflammatory cytokines, chemokines, autoantibodies, mediators (e.g. NO, lipids)
  •   cytokine induction of destructive enzymes, chiefly matrix metalloproteinases (MMP)
  •   tissue damage and fibrosis

 ⇒ The production of pro-inflammatory genes is mainly regulated at the transcriptional level.

 Screening systems

Reporter gene-Assays in human cells

binding sites for single transcription factors in front of a minimal promoter:

e. g. NF-kB, AP-1, STAT1, STAT2, STAT3, STAT6, NF-AT, SMAD2/3, ß-Catenin/TCF4 (Wnt), Glucocorticoid-receptor, PPAR-gamma (activation).

  • investigation of single signal transduction pathways
  • testing for specificity
  • assays for transactivation or transrepression of pathways
  • 3-UTR reporter for characterization of miRNAs

Reporter gene assays with natural human promoters of disease-relevant genes:

  • Activation and binding of all functional TFs to the regulatory sites in the respective promotor after induction with an appropriate pro-inflammatory stimulus (e. g. LPS/IFN-γ or cytokines)
  • follow-up screenings
  • fermentation of fungi and cyanobacteria
  • identification of compounds by bio-activity guided isolation
  • mode-of-action studies and target identification

    

 


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