Phosphodiesterases as Drug Targets

Volume 204 of the series Handbook of Experimental Pharmacology pp 135-149


A Fission Yeast-Based Platform for Phosphodiesterase Inhibitor HTSs and Analyses of Phosphodiesterase Activity

  • Didem DemirbasAffiliated withBiology Department, Boston College
  • , Ozge CeyhanAffiliated withBiology Department, Boston College
  • , Arlene R. WymanAffiliated withBiology Department, Boston College
  • , Charles S. HoffmanAffiliated withBiology Department, Boston College Email author 

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Fission yeast strains have been engineered so that their growth behavior reflects the activity of heterologous cyclic nucleotide phosphodiesterases (PDEs). These strains can be used in High-Throughput Screens (HTSs) for PDE inhibitors that possess “drug-like” characteristics, displaying activity in a growth stimulation assay over a 48-h period. Through three generations of development, a collection of strains expressing 10 of the 11 mammalian PDE families that is appropriate for small molecule inhibitor screening has been generated in our laboratory. Strains unable to synthesize cyclic nucleotides allow characterization of PDE activity in that the enzyme’s potency is reflected in the amount of either cAMP or cGMP that must be added to the growth medium to stimulate cell growth. In the future, this system could be used to screen cDNA libraries for biological regulators of target PDEs and for the construction of strains that co-express PDEs and associated regulatory proteins to facilitate molecular and genetic studies of their functions and, in particular, to identify whether different PDE-partner protein complexes show distinct patterns of inhibitor sensitivity.


cAMP Cell-based assay cGMP High throughput Inhibitors Phosphodiesterase PKA Schizosaccharomyces pombe