Elsevier

Drug Discovery Today

Volume 10, Issue 22, 15 November 2005, Pages 1503-1519
Drug Discovery Today

Review
Keynote review: Phosphodiesterase-4 as a therapeutic target

https://doi.org/10.1016/S1359-6446(05)03622-6Get rights and content

Cyclic AMP (cAMP) is a key second messenger in all cells. It is compartmentalized within cells and its levels are controlled, as a result of spatially discrete signaling cassettes controlling its generation, detection and degradation. Underpinning compartmentalized cAMP signaling are ∼20 members of the phosphodiesterase-4 (PDE4) family. The selective inhibition of this family generates profound, functional effects and PDE4 inhibitors are currently under development to provide potential, novel therapeutics for the treatment of inflammatory diseases, such as asthma, chronic obstructive pulmonary disease and psoriasis, as well as treating depression and serving as cognitive enhancers. Here, we delineate the range of PDE4 isoforms, their role in signaling, their structural biology and related preclinical and clinical pharmacology.

Section snippets

Functional significance of phosphodiesterase-4 isoforms

Cyclic nucleotide phosphodiesterases (PDEs) provide the only route for degrading cyclic AMP (cAMP), a key second messenger inside cells, thus providing a pivotal means of regulating cAMP levels. Their importance is emphasized by the multiplicity of cAMP-hydrolyzing PDEs, encoded by the human genome, and their high conservation between species and during the selective pressures of evolution. Of these, the multi-gene phosphodiesterase-4 (PDE4) family has attracted considerable attention over the

Catalyitic domain structure

The crystal structure of the apo catalytic domain of PDE4B [68] reveals a compact α-helical structure consisting of 16 helices divided into three subdomains (Figure 2a). The active site forms a deep pocket located at the junction of the three subdomains and is lined with highly conserved residues (Figure 2b). A binuclear metal ion center, where Zn2+ is coordinated by conserved, paired histidines and aspartates and two water molecules, is found at the wider side of the active site. Mg2+ is also

Effects of PDE4 inhibition in leukocytes

Tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine that is produced largely by monocytes, macrophages and T cells, is an important drug target in rheumatoid arthritis, ankylosing spondylitis, Crohn's disease and psoriasis. TNF-α production by peripheral blood monocytes and T cells is inhibited by rolipram [74, 75]. In monocytes this inhibition is accompanied by the elevation of intracellular cAMP and the activation of PKA, effects that are synergistically enhanced by the addition of

Conclusions

The plethora of PDE4 isoforms and their widespread expression pattern could be looked upon as a strength and a weakness of PDE4 as a target for drug development. A major challenge will be to refine PDE4 inhibitors to maximize therapeutic efficacy in specific disease states. Thus, future developments are probably going to focus on the ability to target specific PDE4 subfamilies and isoforms. By doing these structural analyses, PDEs are positioned to play a key role in the identification of

Acknowledgements

MDH thanks the Medical Research Council (UK) for financial support. KYJZ would like to thank his colleagues at Plexxikon for their generous support and stimulating discussions.

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  • Cited by (0)

    1

    Miles D. Houslay

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    Miles Houslay is Gardiner Professor of Biochemistry at the University of Glasgow, UK. He obtained his first degree in Biochemistry at the University of Wales in Cardiff, UK and gained his PhD at the University of Cambridge, UK. He has held faculty positions at the Universities of Cambridge (UK) and Manchester (UK). He has been involved in cell signaling research since its inception. His current research interest is focused on the role of phosphodiesterase-4 isoforms in underpinning cyclic AMP compartmentalization and cross-talk processes and the potential for identifying novel therapeutic opportunities.

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    Peter Schafer

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    Peter Schafer is Associate Director of Biology at Celgene in Summit, USA. He obtained his BS in Biological Chemistry from the University of Chicago, USA and his PhD in Biochemistry, Molecular Biology and Cell Biology from Northwestern University. He has conducted research at the R.W. Johnson Pharmaceutical Research Institute on the role of p38 MAP kinase in inflammation. His current efforts in drug discovery focus on PDE4 inhibitors, immunomodulation and angiogenesis.

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    Kam Y.J. Zhang

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    Kam Zhang is Director of Structural Biology at Plexxikon in Berkeley, USA. He obtained his BS in Chemistry from Peking University, China and his PhD in Protein Crystallography from the University of York, UK. He has conducted research at UCLA, Fred Hutchinson Cancer Research Center and at Structural Genomix on crystallographic phasing, protein folding, apoptosis and crystallographic automation. His current work focuses on scaffold-based drug discovery for various therapeutic targets, including phosphodiesterases, using high throughput co-crystallography.

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