Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors.
Phosphodiesterase 5 (PDE5) is one of the most well-studied phosphodiesterases (PDEs) that specifically targets cGMP typically generated by nitric oxide (NO)-mediated activation of the soluble guanylyl cyclase. Given the crucial role of cGMP generated through the activation of this cellular signaling pathway in a variety of physiologically processes, pharmacological inhibition of PDE5 has been demonstrated to have several therapeutic applications including erectile dysfunction and pulmonary arterial hypertension. While they are designed to inhibit PDE5, the inhibitors show different affinities and specificities against all PDE subtypes. Additionally, they have been shown to induce allosteric structural changes in the protein. These are mostly attributed to their chemical structure and, therefore, binding interactions with PDE catalytic domains. Therefore, understanding how these inhibitors interact with PDE5 and the structural basis of their selectivity is critically important for the design of novel, highly selective PDE5 inhibitors. Here, we review the structure of PDE5, how its function is regulated, and discuss the clinically available inhibitors that target phosphodiesterase 5, aiming to better understand the structural bases of their affinity and specificity. We also discuss the therapeutic indications of these inhibitors and the potential of repurposing for a wider range of clinical applications.
['Ahmed|Wesam S|WS|', 'Geethakumari|Anupriya M|AM|', 'Biswas|Kabir H|KH|']
D000818:Animals D020134:Catalytic Domain D006152:Cyclic GMP D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 D006801:Humans D007527:Isoenzymes D058986:Phosphodiesterase 5 Inhibitors D010766:Phosphorylation D011487:Protein Conformation D015398:Signal Transduction D013329:Structure-Activity Relationship
Therapeutic applications Phosphodiesterase 5 (PDE5) Cardiovascular diseases Clinical indications Cyclic guanosine monophosphate (cGMP) Pharmacological inhibitors