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

This article has been updated

Abstract

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.

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Fig. 1: Cyclic nucleotide signalling pathways.
Fig. 2: The 21 PDE genes, grouped into families.
Fig. 3: Mechanisms that activate PDE catalytic activity.
Fig. 4: Methods for targeting PDE signalling with increasing specificity.
Fig. 5: PDE regulation by post-translational modification.

Change history

  • 15 August 2019

    The acknowledgements were amended to include the grants supporting the work of G.S.B. and to indicate that G.S.T is a fellow of the Astrazeneca postdoctoral programme.

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Acknowledgements

Work supported by 1R01MH101130 and 1R01AG061200 (M.P.K.). G.S.B. is supported by grants from the British Heart Foundation (BHF/TARGETPDE/PG/17/26/32881) and Medical Research Council (MC-PC-13063 and MC-PC-15039). G.S.T. is a fellow of the AstraZeneca postdoctoral programme.

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Correspondence to Michy P. Kelly.

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G.S.B. is co-founder and director of Portage Glasgow Limited. The other authors declare no competing interests. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Glossary

Nanodomains

Subcellular compartments within which intracellular signalling is discretely localized largely due to anchoring of molecules within macromolecular complexes.

Acrodysostosis

A rare congenital disorder characterized by abnormal bone growth leading to very short fingers/toes, underdeveloped facial bones, a small nose and short stature, as well as developmental and intellectual disabilities.

Cerebral hypofusion

Reduces blood flow to/throughout the brain.

Coronary stent stenosis

A gradual re-narrowing of a coronary artery leading to restricted blood flow that occurs after angioplasty and stenting have been performed to relieve a prior blockage.

Dystonia

A movement disorder characterized by repetitive or twisting movements due to involuntary muscle contraction.

Lichen planus

An inflammatory condition characterized by purplish, itchy bumps on/around the skin, hair, nails and mucous membrane (due to unknown causes).

Dyskinesias

Diminished voluntary movements or uncontrollable involuntary movements (for example, tics or chorea).

Retinitis pigmentosa

A rare genetic disorder characterized by black pigmentation and retinal degeneration.

Trans-capping

The process whereby the regulatory domains from one phosphodiesterase (PDE) enzyme physically bind — and, thus, block substrate access to — the C-terminal catalytic domain of another PDE molecule.

Phosphodegron

A phosphorylation motif that alters the rate of degradation by attracting ubiquitin ligases to the phosphorylated protein.

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Baillie, G.S., Tejeda, G.S. & Kelly, M.P. Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond. Nat Rev Drug Discov 18, 770–796 (2019). https://doi.org/10.1038/s41573-019-0033-4

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