Kelly Evan D, Ranek Mark J, Zhang Manling, Kass David A, Muller Grace K
Department of Cell and Molecular Physiology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, USA; email:
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Annu Rev Pharmacol Toxicol. 2025 Jan;65(1):415-441. doi: 10.1146/annurev-pharmtox-031524-025239. Epub 2024 Dec 17.
Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides. While the 11 PDE subfamilies share common features, key differences confer signaling specificity. The differences include substrate selectivity, enzymatic activity regulation, tissue expression, and subcellular localization. Selective inhibitors of each subfamily have elucidated the protean role of PDEs in normal cell function. PDEs are also linked to diseases, some of which affect the immune, cardiac, and vascular systems. Selective PDE inhibitors are clinically used to treat these specific disorders. Ongoing preclinical studies and clinical trials are likely to lead to the approval of additional PDE-targeting drugs for therapy in human disease. In this review, we discuss the structure and function of PDEs and examine current and evolving therapeutic uses of PDE inhibitors, highlighting their mechanisms and innovative applications that could further leverage this crucial family of enzymes in clinical settings.
磷酸二酯酶（PDEs）是一类水解环核苷酸的酶超家族。虽然11个PDE亚家族具有共同特征，但关键差异赋予了信号传导特异性。这些差异包括底物选择性、酶活性调节、组织表达和亚细胞定位。每个亚家族的选择性抑制剂已阐明了PDEs在正常细胞功能中的多种作用。PDEs也与疾病相关，其中一些疾病会影响免疫、心脏和血管系统。选择性PDE抑制剂在临床上用于治疗这些特定疾病。正在进行的临床前研究和临床试验可能会导致更多靶向PDE的药物获批用于人类疾病治疗。在本综述中，我们讨论了PDEs的结构和功能，并研究了PDE抑制剂当前及不断发展的治疗用途，重点介绍了它们的作用机制以及创新应用，这些应用可能会在临床环境中进一步利用这一关键酶家族。
