A considerable number of human diseases have an inflammatory component, and a key mediator of immune activation and inflammation is inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO) from l‐arginine. Overexpressed or dysregulated iNOS has been implicated in numerous pathologies including sepsis, cancer, neurodegeneration, and various types of pain. Extensive knowledge has been accumulated about the roles iNOS plays in different tissues and organs. Additionally, X‐ray crystal and cryogenic electron microscopy structures have shed new insights on the structure and regulation of this enzyme. Many potent iNOS inhibitors with high selectivity over related NOS isoforms, neuronal NOS, and endothelial NOS, have been discovered, and these drugs have shown promise in animal models of endotoxemia, inflammatory and neuropathic pain, arthritis, and other disorders. A major issue in iNOS inhibitor development is that promising results in animal studies have not translated to humans; there are no iNOS inhibitors approved for human use. In addition to assay limitations, both the dual modalities of iNOS and NO in disease states (ie, protective vs harmful effects) and the different roles and localizations of NOS isoforms create challenges for therapeutic intervention. This review summarizes the structure, function, and regulation of iNOS, with focus on the development of iNOS inhibitors (historical and recent). A better understanding of iNOS’ complex functions is necessary before specific drug candidates can be identified for classical indications such as sepsis, heart failure, and pain; however, newer promising indications for iNOS inhibition, such as depression, neurodegenerative disorders, and epilepsy, have been discovered.

中文翻译：

---

诱导型一氧化氮合酶：调节、结构和抑制。


相当多的人类疾病都含有炎症成分，而免疫激活和炎症的关键介质是诱导型一氧化氮合酶 (iNOS)，它从L-精氨酸产生一氧化氮 (NO)。 iNOS 过度表达或失调与多种病理有关，包括脓毒症、癌症、神经退行性变和各种类型的疼痛。关于 iNOS 在不同组织和器官中的作用，人们已经积累了广泛的知识。此外，X 射线晶体和低温电子显微镜结构为这种酶的结构和调控提供了新的见解。人们已经发现了许多对相关 NOS 亚型、神经元 NOS 和内皮 NOS 具有高选择性的强效 iNOS 抑制剂，并且这些药物在内毒素血症、炎症和神经性疼痛、关节炎和其他疾病的动物模型中显示出良好的前景。 iNOS 抑制剂开发的一个主要问题是动物研究中令人鼓舞的结果尚未转化为人类；目前还没有批准用于人类使用的 iNOS 抑制剂。除了检测限制之外，iNOS 和 NO 在疾病状态下的双重模式（即保护作用与有害作用）以及 NOS 亚型的不同作用和定位都给治疗干预带来了挑战。本综述总结了 iNOS 的结构、功能和调控，重点关注 iNOS 抑制剂的发展（历史和近期）。在确定针对脓毒症、心力衰竭和疼痛等经典适应症的特定候选药物之前，有必要更好地了解 iNOS 的复杂功能；然而，已经发现了 iNOS 抑制的新的有希望的适应症，例如抑郁症、神经退行性疾病和癫痫。