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Competitive Genomic Screens of Barcoded Yeast Libraries
Published on: August 11, 2011
Identification of biologically active PDE11-selective inhibitors using a yeast-based high-throughput screen
Ozge Ceyhan1, Kivanc Birsoy, Charles S Hoffman
1Biology Department, Boston College, Chestnut Hill, MA 02467, USA.
Chemistry & Biology
|January 31, 2012
Summary
Researchers discovered potent cyclic nucleotide phosphodiesterase 11 (PDE11) inhibitors using a high-throughput screen. These compounds aid in studying adrenal function and developing treatments for adrenal insufficiencies.
Area of Science:
- Biochemistry
- Enzymology
- Pharmacology
Background:
- The biological functions of cyclic nucleotide phosphodiesterase 11 (PDE11) are not well understood.
- A lack of selective PDE11 inhibitors hinders research into its roles.
Purpose of the Study:
- To identify potent and selective inhibitors of PDE11.
- To develop chemical tools for studying PDE11 in cellular models.
- To establish leads for potential therapeutics targeting adrenal insufficiency.
Main Methods:
- Conducted a high-throughput screen (HTS) of approximately 200,000 compounds.
- Utilized a yeast-based growth assay to identify PDE11 inhibitors.
- Validated inhibitor activity in human adrenocortical cells.
Main Results:
- Identified four potent and selective PDE11 inhibitors.
- One inhibitor and its analogs increased cAMP and cortisol levels in human adrenocortical cells.
- Results align with genetic studies linking PDE11 to adrenal function.
Conclusions:
- The identified compounds are valuable tools for investigating PDE11's role in cellular processes.
- These inhibitors serve as promising leads for developing treatments for adrenal insufficiencies.
- The yeast-based HTS platform is effective for discovering biologically active PDE inhibitors.
