Advances in targeting cyclic nucleotide phosphodiesterases

• Published in: Nature reviews. Drug discovery Vol. 13; no. 4; pp. 290 - 314
• Main Authors: Maurice, Donald H., Ke, Hengming, Ahmad, Faiyaz, Wang, Yousheng, Chung, Jay, Manganiello, Vincent C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2014; Nature Publishing Group
• Subjects: 631/154; Animals; Biomedicine; Biotechnology; Cancer Research; Cyclic AMP - metabolism; Cyclic GMP - metabolism; Drug Design; Humans; Medicinal Chemistry; Molecular Medicine; Molecular Targeted Therapy; Pharmacology/Toxicology; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - metabolism; review-article; Signal Transduction - drug effects
• ISSN: 1474-1776; 1474-1784
• DOI: 10.1038/nrd4228

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.
Inhibitors of cyclic nucleotide phosphodiesterases (PDEs), which regulate concentrations of the key signalling intermediates cAMP and cGMP, are well established as drugs for disorders including erectile dysfunction and pulmonary hypertension. This article discusses how recent understanding of the roles of individual PDEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways is aiding the development of more sophisticated strategies to target individual PDE variants.
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.