College of Health & Life Sciences, Hamad Bin Khalifa University, Education City, Qatar Foundation, Doha, 34110, Qatar.
College of Health & Life Sciences, Hamad Bin Khalifa University, Education City, Qatar Foundation, Doha, 34110, Qatar.
Biomed Pharmacother. 2021 Feb;134:111128. doi: 10.1016/j.biopha.2020.111128. Epub 2020 Dec 18.
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.
磷酸二酯酶 5（PDE5）是研究最为透彻的磷酸二酯酶（PDEs）之一，其特异地靶向通常由一氧化氮（NO）介导的可溶性鸟苷酸环化酶激活产生的环鸟苷酸（cGMP）。鉴于通过这种细胞信号通路的激活产生的 cGMP 在多种生理过程中的关键作用，PDE5 的药理学抑制已被证明具有多种治疗应用，包括勃起功能障碍和肺动脉高压。虽然它们旨在抑制 PDE5，但抑制剂对所有 PDE 亚型的亲和力和特异性不同。此外，它们已被证明会诱导蛋白质的变构结构变化。这些主要归因于它们的化学结构，因此与 PDE 催化结构域的结合相互作用。因此，了解这些抑制剂如何与 PDE5 相互作用以及它们选择性的结构基础对于设计新型、高选择性 PDE5 抑制剂至关重要。在这里，我们回顾了 PDE5 的结构、其功能如何被调节，并讨论了靶向磷酸二酯酶 5 的临床可用抑制剂，旨在更好地理解它们亲和力和特异性的结构基础。我们还讨论了这些抑制剂的治疗适应症以及更广泛的临床应用的重新定位的潜力。
