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Yeast-based assays for screening 11β-HSD1 inhibitors
Rosario Vanella1, Roberta Callari1,2, Anna Weston1
1University of Applied Sciences Northwestern Switzerland, Gründenstrasse 40, 4132, Muttenz, Switzerland.
Microbial Cell Factories
|March 17, 2016
Summary
We developed novel yeast-based assays for screening 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors. These cost-efficient assays enable rapid identification of potential therapeutics for metabolic syndrome and skin aging.
Area of Science:
- Biochemistry
- Molecular Biology
- Yeast Synthetic Biology
Background:
- Intracellular glucocorticoid metabolism is crucial for metabolic syndrome pathogenesis.
- 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates active cortisol levels and is a therapeutic target.
- 11β-HSD1 inhibitors show potential for treating metabolic syndrome and skin aging.
Purpose of the Study:
- To construct and validate yeast cell-based assays for screening 11β-HSD1 inhibitors.
- To provide a cost-efficient and high-throughput screening method for novel 11β-HSD1 inhibitors.
Main Methods:
- Utilized Saccharomyces cerevisiae as a host for expressing human 11β-HSD1.
- Developed two genetically encoded fluorescent assays for intracellular screening.
- Validated assays using known 11β-HSD1 inhibitors (carbenoxolone, tanshinone IIA).
- Enhanced assay sensitivity by inhibiting the Pdr5p transporter.
Main Results:
- Successfully established yeast strains expressing 11β-HSD1 with measurable fluorescent outputs.
- Demonstrated correlation between 11β-HSD1 inhibition and fluorescence changes.
- Developed assays with distinct read-outs (fluorescence decrease or stabilization of yEGFP).
- Achieved up to 60-fold improvement in sensitivity to cortisone by inhibiting Pdr5p.
Conclusions:
- Yeast assay strains offer a cost-effective and user-friendly alternative for 11β-HSD1 inhibitor screening.
- Assays facilitate rapid selection of cell-permeable inhibitors for further development.
- Potential integration into yeast synthetic biology platforms for simultaneous synthesis and screening.
