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Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases

Research output: Contribution to journalArticle

Faisa Omar, Jane E. Findlay, Gemma Carfray, Robert W. Allcock, Zhong Jiang, Caitlin Moore, Amy L. Muir, Morgane Lannoy, Bracy A. Fertig, Deborah Mai, Jonathan P. Day, Graeme Bolger, George S. Baillie, Erik Schwiebert, Enno Klussmann, Nigel J. Pyne, Albert C.M. Ong, Keith Bowers, Julia M. Adam, David R. Adams & 2 more Miles D. Houslay, David J.P. Henderson

Original languageEnglish
Pages (from-to)13320-13329
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number27
Early online date17 Jun 2019
DOIs
Accepted/In press23 May 2019
E-pub ahead of print17 Jun 2019
Published1 Jul 2019

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Abstract

Cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) enzymes degrade cAMP and underpin the compartmentalization of cAMP signaling through their targeting to particular protein complexes and intracellular locales. We describe the discovery and characterization of a small-molecule compound that allosterically activates PDE4 long isoforms. This PDE4-specific activator displays reversible, noncompetitive kinetics of activation (increased Vmax with unchanged Km), phenocopies the ability of protein kinase A (PKA) to activate PDE4 long isoforms endogenously, and requires a dimeric enzyme assembly, as adopted by long, but not by short (monomeric), PDE4 isoforms. Abnormally elevated levels of cAMP provide a critical driver of the underpinning molecular pathology of autosomal dominant polycystic kidney disease (ADPKD) by promoting cyst formation that, ultimately, culminates in renal failure. Using both animal and human cell models of ADPKD, including ADPKD patient-derived primary cell cultures, we demonstrate that treatment with the prototypical PDE4 activator compound lowers intracellular cAMP levels, restrains cAMP-mediated signaling events, and profoundly inhibits cyst formation. PDE4 activator compounds thus have potential as therapeutics for treating disease driven by elevated cAMP signaling as well as providing a tool for evaluating the action of long PDE4 isoforms in regulating cAMP-mediated cellular processes.

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