Abstract
PDE4 is one of eleven known cyclic nucleotide phosphodiesterase families and plays a pivotal role in mediating hydrolytic degradation of the important cyclic nucleotide second messenger, cyclic 3′5′ adenosine monophosphate (cAMP). PDE4 inhibitors are known to have anti-inflammatory properties, but their use in the clinic has been hampered by mechanism-associated side effects that limit maximally tolerated doses. In an attempt to initiate the development of better-tolerated PDE4 inhibitors we have surveyed existing approved drugs for PDE4-inhibitory activity. With this objective, we utilised a high-throughput computational approach that identified moexipril, a well tolerated and safe angiotensin-converting enzyme (ACE) inhibitor, as a PDE4 inhibitor. Experimentally we showed that moexipril and two structurally related analogues acted in the micro molar range to inhibit PDE4 activity. Employing a FRET-based biosensor constructed from the nucleotide binding domain of the type 1 exchange protein activated by cAMP, EPAC1, we demonstrated that moexipril markedly potentiated the ability of forskolin to increase intracellular cAMP levels. Finally, we demonstrated that the PDE4 inhibitory effect of moexipril is functionally able to induce phosphorylation of the small heat shock protein, Hsp20, by cAMP dependent protein kinase A. Our data suggest that moexipril is a bona fide PDE4 inhibitor that may provide the starting point for development of novel PDE4 inhibitors with an improved therapeutic window.
Highlights
The escalating costs and diminishing returns of drug development have fuelled a growing focus on drug repositioning in recent years [1]
Discrete intracellular targeting of individual phosphodiesterase 4 (PDE4) isoforms is most often directed by a ‘‘postcode’’ sequence within their unique N-terminal domains [10], which are responsible for promoting many of the protein– protein and protein–lipid interactions that act to anchor PDE4s to signalling nodes in sub-cellular compartments [6]
Under the conditions of our in vitro studies, the elevation in global cyclic AMP (cAMP) triggered by moexipril and analogues resulted in downstream signalling events driven by the cAMP-effector protein, protein-kinase A (PKA), we studied a phosphorylation event recently attributed to the kinase
Summary
The escalating costs and diminishing returns of drug development have fuelled a growing focus on drug repositioning in recent years [1]. As annual approvals of new molecular entities (NMEs) dwindle in the face of increasing economic and regulatory pressures [2], greater emphasis is being placed on the development of systematic approaches for identification of compounds with repositioning potential, including the application of in silico structure-based and chemoinformatic methodologies [3,4,5] We have used such approaches to find novel inhibitors of the important cAMP hydrolyzing phosphodiesterase 4 (PDE4) enzyme family, which has been implicated in the pathophysiology underlying a range of diseases and conditions that include schizophrenia, stroke and asthma [6]. Discrete intracellular targeting of individual PDE4 isoforms is most often directed by a ‘‘postcode’’ sequence within their unique N-terminal domains [10], which are responsible for promoting many of the protein– protein and (in one case) protein–lipid interactions that act to anchor PDE4s to signalling nodes in sub-cellular compartments [6]
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