Therapeutic targeting of 3',5'-cyclic nucleotide phosphodiesterases: inhibition and beyond

Nat Rev Drug Discov. 2019 Oct;18(10):770-796. doi: 10.1038/s41573-019-0033-4. Epub 2019 Aug 6.


Phosphodiesterases (PDEs), enzymes that degrade 3',5'-cyclic nucleotides, are being pursued as therapeutic targets for several diseases, including those affecting the nervous system, the cardiovascular system, fertility, immunity, cancer and metabolism. Clinical development programmes have focused exclusively on catalytic inhibition, which continues to be a strong focus of ongoing drug discovery efforts. However, emerging evidence supports novel strategies to therapeutically target PDE function, including enhancing catalytic activity, normalizing altered compartmentalization and modulating post-translational modifications, as well as the potential use of PDEs as disease biomarkers. Importantly, a more refined appreciation of the intramolecular mechanisms regulating PDE function and trafficking is emerging, making these pioneering drug discovery efforts tractable.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • Animals
  • Humans
  • Molecular Targeted Therapy*
  • Phosphodiesterase Inhibitors / therapeutic use*
  • Signal Transduction / drug effects*


  • Phosphodiesterase Inhibitors
  • 3',5'-Cyclic-AMP Phosphodiesterases