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

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. AdamsMiles D. Houslay, David J. P. Henderson

Research output: Contribution to journalArticle

14 Citations (Scopus)
16 Downloads (Pure)

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 characteriza- tion 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 domi- nant 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 pri- mary cell cultures, we demonstrate that treatment with the prototyp- ical 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 signal- ing as well as providing a tool for evaluating the action of long PDE4 isoforms in regulating cAMP-mediated cellular processes.
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
Publication statusPublished - 2 Jul 2019

Keywords

  • ADPKD
  • Cyclic AMP
  • PDE4
  • PDE4 activator
  • Phosphodiesterase

ASJC Scopus subject areas

  • General

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