Short PDE4 Isoforms as Drug Targets in Disease

The second messenger, cyclic adenosine monophosphate (cAMP), is a master regulator of signal transduction that maintains cell homeostasis. A fine balance between cAMP synthesis by adenylyl cyclase and degradation phosphodiesterases (PDEs) underpins receptor-specific responses. As multiple receptors rely on for signaling, PDEs shape three-dimensional, localized gradients the nucleotide to drive appropriate signaling cascades. Of 11 PDE families, PDE4, which comprises long, short, supershort isoforms dead-short isoform, great interest due its implication in disease. Aberrant PDE4 expression post-translational modifications are hallmarks several clinical indications curative treatment not yet available. While some PDE4-specific small molecule inhibitors directed against active site approved use, they limited severe side effects owing high degree conservation catalytic domain over 20 unique isoforms. Some attempts use different modular structure exists long shorter now bearing success. However, these exclusively aimed at isoforms, have been focus majority research this area. Here, we summarised literature lesser-studied short provide record discovery, regulation, disease relevance class enzymes represent an untapped target specific inhibition future.