Institute of Physiology, University of Würzburg, Röntgenring 9, D-97070, Würzburg, Germany.
Pharmaceuticals, Research and Early Development, Pharma Research Center, Bayer AG, Aprather Weg 18a, D-42096 , Wuppertal, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2023 Aug;396(8):1669-1686. doi: 10.1007/s00210-023-02484-8. Epub 2023 Apr 20.
Increasing cGMP is a unique therapeutic principle, and drugs inhibiting cGMP-degrading enzymes or stimulating cGMP production are approved for the treatment of various diseases such as erectile dysfunction, coronary artery disease, pulmonary hypertension, chronic heart failure, irritable bowel syndrome, or achondroplasia. In addition, cGMP-increasing therapies are preclinically profiled or in clinical development for quite a broad set of additional indications, e.g., neurodegenerative diseases or different forms of dementias, bone formation disorders, underlining the pivotal role of cGMP signaling pathways. The fundamental understanding of the signaling mediated by nitric oxide-sensitive (soluble) guanylyl cyclase and membrane-associated receptor (particulate) guanylyl cyclase at the molecular and cellular levels, as well as in vivo, especially in disease models, is a key prerequisite to fully exploit treatment opportunities and potential risks that could be associated with an excessive increase in cGMP. Furthermore, human genetic data and the clinical effects of cGMP-increasing drugs allow back-translation into basic research to further learn about signaling and treatment opportunities. The biannual international cGMP conference, launched nearly 20 years ago, brings all these aspects together as an established and important forum for all topics from basic science to clinical research and pivotal clinical trials. This review summarizes the contributions to the "10th cGMP Conference on cGMP Generators, Effectors and Therapeutic Implications," which was held in Augsburg in 2022 but will also provide an overview of recent key achievements and activities in the field of cGMP research.
增加 cGMP 是一种独特的治疗原则,抑制 cGMP 降解酶或刺激 cGMP 产生的药物已被批准用于治疗各种疾病,如勃起功能障碍、冠状动脉疾病、肺动脉高压、慢性心力衰竭、肠易激综合征或软骨发育不全。此外,增加 cGMP 的治疗方法正在进行临床前研究或临床开发,用于治疗相当广泛的其他适应症,例如神经退行性疾病或不同形式的痴呆、骨形成障碍,这强调了 cGMP 信号通路的关键作用。从分子和细胞水平以及体内(特别是在疾病模型中)对一氧化氮敏感(可溶性)鸟苷酸环化酶和膜相关受体(颗粒状)鸟苷酸环化酶介导的信号的基本理解是充分利用治疗机会和可能与 cGMP 过度增加相关的潜在风险的关键前提。此外,人类遗传数据和增加 cGMP 的药物的临床效果允许反向翻译到基础研究中,以进一步了解信号和治疗机会。这个两年一次的国际 cGMP 会议在近 20 年前启动,将所有这些方面汇集在一起,成为一个基础科学到临床研究和关键临床试验的既定和重要论坛。这篇综述总结了 2022 年在奥格斯堡举行的“第十届 cGMP 会议:cGMP 生成剂、效应器和治疗意义”的贡献,同时也概述了 cGMP 研究领域的最新关键成就和活动。