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Advances in targeting cyclic nucleotide phosphodiesterases

Nature Reviews Drug Discovery volume 13, pages 290–314 (2014)Cite this article

Subjects

Key Points

  • The nucleotides cAMP and cGMP both regulate myriad effects in virtually all animal cells. These actions are coordinated through protein kinase A (PKA), PKG, exchange factor directly activated by cAMP1 (EPAC1), EPAC2 and cyclic nucleotide-gated ion channels.

  • Intracellular levels of cAMP and cGMP are controlled through their synthesis by nucleotidyl cyclases and their hydrolysis by enzymes of the cyclic nucleotide phosphodiesterase (PDE) family of enzymes. Eleven families of PDEs, containing at least 25 genes, are each defined based on differences in their sequence, substrate specificity, regulatory characteristics, inhibitor sensitivity and tissue distribution.

  • PDEs have consistently been considered to be key therapeutic targets, from both clinical and economic perspectives, and numerous PDE inhibitors have been developed for use in the treatment of many diseases and conditions.

  • The emergence of the structure-based design of novel specific inhibitors and of allosteric modulators, which take advantage of interactions between regulatory and catalytic structures in these enzymes, has further increased the ability to target individual enzymes from this large family.

  • Most recently, crucial roles of individual PDEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways have been established by the concept that PDEs are incorporated into localized macromolecular complexes with cyclic nucleotide effectors — structures termed signalosomes. This knowledge has spurred the development of more sophisticated strategies to target individual PDE variants.

  • The incorporation of individual PDEs from distinct families, with their distinct intrinsic characteristics and regulatory properties, into signalosomes allows crosstalk between cyclic nucleotides and other signalling networks and systems.

  • Advances in identifying protein components of individual signalosomes and in establishing how these interact are beginning to permit the targeting of intermolecular protein–protein interactions between PDEs and their regulatory partners. There is enormous hope and confidence that this will hasten the development of signalosome disruptors that target individual PDEs and provide treatment for a broad range of clinical indications.

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) catalyse the hydrolysis of cyclic AMP and cyclic GMP, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signalling pathways and, consequently, myriad biological responses in health and disease. Currently, a small number of PDE inhibitors are used clinically for treating the pathophysiological dysregulation of cyclic nucleotide signalling in several disorders, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication and chronic obstructive pulmonary disease. However, pharmaceutical interest in PDEs has been reignited by the increasing understanding of the roles of individual PDEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways, by the structure-based design of novel specific inhibitors and by the development of more sophisticated strategies to target individual PDE variants.

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Figure 1: Structure and domain organization of 11 mammalian PDE families.
Figure 2: Binding of substrates and inhibitors to the active site of PDEs.
Figure 3: PDE-containing signalosomes couple cAMP–PKA signalling to myocardial contractility.
Figure 4: Human arterial endothelial cells construct two distinct PDE- and EPAC-based signalosomes to regulate, spatially and functionally, integrin- and vascular endothelial cadherin-based adhesions, respectively.
Figure 5: Allosteric modulation of PDE2 and PDE4.

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References

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Acknowledgements

V.M., J.C. and F.A. were supported by the National Heart, Lung and Blood Institute (NHLBI) Intramural research Program at the US National Institutes of Health (NIH) in Bethesda, Maryland, USA. Research funding for D.H.M. is from the Canadian Institutes of Health Research (CIHR).

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Authors and Affiliations

  1. Biomedical and Molecular Sciences, Queen's University, Kingston, K7L3N6, Ontario, Canada

    Donald H. Maurice

  2. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, 27599, North Carolina, USA

    Hengming Ke

  3. Cardiovascular and Pulmonary Branch, The National Heart, Lung and Blood Institute, US National Institutes of Health, Bethesda, 20892, Maryland, USA

    Faiyaz Ahmad & Vincent C. Manganiello

  4. Beijing Technology and Business University, Beijing, 100048, China

    Yousheng Wang

  5. Genetics and Developmental Biology Center, The National Heart, Lung and Blood Institute, US National Institutes of Health, Bethesda, 20892, Maryland, USA

    Jay Chung

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Supplementary information

Supplementary information S1 (figure)

(A,B) Binding of PDE4 inhibitors to the catalytic domain. (PDF 2715 kb)

Supplementary information S2 (figure)

Application of structure-based drug design to generate selective PDE 9A (A, B) and PDE10A inhibitors. (PDF 2816 kb)

Supplementary information S3 (table)

Compartmented PDE signaling in mammalian cells. (PDF 182 kb)

Glossary

Cyclic nucleotide phosphodiesterase

(PDE). A large gene superfamily of isozymes that catalyse the hydrolysis of the important intracellular messengers cAMP and cGMP.

Signalosomes

Localized macromolecular complexes, formed via protein–protein interactions, that contain cyclic nucleotide effectors and regulate the subcellular compartmentalization of specific cyclic nucleotide signalling pathways. The incorporation of specific phosphodiesterases (PDEs) into signalosomes has established the crucial roles of individual PDEs in regulating specific cyclic nucleotide signalling pathways. This knowledge has spurred the development of more sophisticated strategies to target individual PDE variants and their interacting partners.

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Maurice, D., Ke, H., Ahmad, F. et al. Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov 13, 290–314 (2014). https://doi.org/10.1038/nrd4228

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