Inducible nitric oxide synthase: Regulation, structure, and inhibition

Abstract

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.

Solid‐Phase Synthesis of Substrate‐Based Dipeptides and Heterocyclic Pseudo‐dipeptides as Potential NO Synthase Inhibitors

“…Overproduction of NO is observed in several pathophysiological states and mainly concerns nNOS and iNOS . Neuronal NOS is involved in stroke and neurodegenerative diseases, while iNOS has been identified as the cause of or an aggravating factor in several human diseases involving an inflammatory state, including septic shock, chronic inflammatory diseases, insulin resistance, cancers, migraine . Thus, nNOS and iNOS are potential therapeutic targets, but the multiple roles of NO complicate the discovery of inhibitors of pharmaceutical interest .…”

“…[8][9][10][11][12] Neuronal NOS is involved in stroke and neurodegenerative diseases, [13,14] while iNOS has been identified as the cause of or an aggravating factor in several human diseases involving an inflammatory state, including septic shock, chronic inflammatory diseases, insulin resistance, cancers, migraine. [15][16][17][18][19][20] Thus, nNOS and iNOS are potential therapeutic targets, but the multiple roles of NO complicate the discovery of inhibitors of pharmaceutical interest. [21] In particular, such inhibitors must be highly selective to preserve the essential eNOS functions.…”

What urologists need to know about ketamine‐induced uropathy: A systematic review

“…Inflammation is confirmed by positive immunohistochemical staining for inflammatory markers (cyclooxygenase‐2, inducible nitric oxide synthase, matrix metallopeptidase‐9, mammalian target of rapamycin, and phosphorylated 40S ribosomal protein S6) 19,24 . Inducible nitric oxide synthase is responsible for the inflammation process because it is related to many cytokines, prostacyclin, prostaglandin E2, and cyclooxygenase pathways, which have severe inflammatory action and increase collagen expression and deposition 25,26 . Ketamine treatment in rats induces direct activation of the cyclooxygenase pathway with prostaglandin‐E2 production and an upregulation of cyclooxygenase‐2 expression in the bladder 27,28 .…”

The Antitumor Efficacy of β-Elemene by Changing Tumor Inflammatory Environment and Tumor Microenvironment

“…When cells are exposed to persistent oxidative stress caused by chronic inflammation, the RNS nitric oxide (NO) induces gene mutation and inactivates key enzymes for DNA damage repair, thereby preventing or impairing DNA repair and exacerbating DNA damage [83,84]. NO is an important inflammatory mediator that is associated with chronic inflammation and cancer and is produced endogenously through different isomerizations of nitric oxide synthase (NOS) during arginine metabolism [85,86]. During inflammation, macrophages and epithelial cells induce iNOS expression.…”

“…Changes iNOS and NO Levels. iNOS, inducible nitric oxide synthase, is a catalytic enzyme that is produced by NOS active nitrogen free radicals in the body [86], and the level of iNOS may be an important indicator of the degree of inflammation in an organism [87]. In the inflammatory microenvironment, macrophages and epithelial cells induce the expression of iNOS, and then, the local iNOS activity in the inflammatory microenvironment is significantly increased quickly, leading to an increase in NO of more than 10 3 times the basal state [139].…”