Mechanism of Inducible Nitric-oxide Synthase Dimerization Inhibition by Novel Pyrimidine Imidazoles

Nagpal, Latika; Haque, Mohammad Mahfuzul; Saha, Amit; Mukherjee, Nirmalya; Ghosh, Arnab; Ranu, Brindaban C.; Stuehr, Dennis J.; Panda, Koustubh

doi:10.1074/jbc.m112.446542

Cited by 29 publications

(20 citation statements)

References 42 publications

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“…Mechanistic studies (spectroscopy and competition binding) performed by Blasko et al later confirmed that pyrimidinylimidazoles do act by coordinating the heme center of iNOS monomers and allosterically blocking dimerization, and it was proposed that the observed selectivity reflects different dimer assembly kinetics in eNOS and nNOS (vs iNOS). It was shown more recently that pyrimidinylimidazoles can also break up active dimers into monomers in cells and that the monomer‐inhibitor complex is irreversible and cannot be converted back into active dimers by added l ‐Arg or H 4 B.…”

Section: Development Of Inos Inhibitorsmentioning

confidence: 99%

Inducible nitric oxide synthase: Regulation, structure, and inhibition

Cinelli

Miley

et al. 2019

Medicinal Research Reviews

524

368

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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.

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Section: Development Of Inos Inhibitorsmentioning

confidence: 99%

Inducible nitric oxide synthase: Regulation, structure, and inhibition

Cinelli

Miley

et al. 2019

Medicinal Research Reviews

524

368

View full text Add to dashboard Cite

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“…Dimerization of iNOS is required for optimal enzymatic activity for which multiple cofactors including calmodulin, heme, FAD, NADPH, FMN and BH4 are important [13]. E. coli K1 interaction with human brain microvascular endothelial cells (HBMEC) induced biopterin levels, which in turn is responsible for increased production of NO [11].…”

Section: Discussionmentioning

confidence: 99%

Escherichia coli K1 induces pterin production for enhanced expression of Fcγ receptor I to invade RAW 264.7 macrophages

Shanmuganathan

Krishnan

et al. 2014

Microbes and Infection

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Macrophages serve as permissive niches for Escherichia coli (E. coli) K1 to attain high grade bacteremia in the pathogenesis of meningitis in neonates. Although pterin levels are a diagnostic marker for immune activation, the role of macrophages in pterin production and in the establishment of meningitis is unknown. Here, we demonstrate that macrophages infected with E. coli K1 produce both neopterin and biopterin through increased expression of GTP-cyclohydrolase 1 (GCH1). Of note, increased production of biopterin enhances the expression of Fc-gamma receptor I (CD64), which in turn, aided the entry of E. coli K1 in macrophages while increased neopterin suppresses reactive oxygen species (ROS), thereby aiding bacterial survival. Inhibition of GCH1 by 2, 4-Diamino-6-hydroxypyrimidine (DAHP) prevented the E. coli K1 induced expression of CD64 in macrophages in vitro and the development of bacteremia in a newborn mouse model of meningitis. These studies suggest that targeting GCH1 could be therapeutic strategy for preventing neonatal meningitis by E. coli K1.

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“…Thus, inhibitors of iNOS dimerization have therapeutic potential in effectively controlling iNOS activity and reducing the high levels of NO produced under pathological conditions (29). Recently, pyrimidine imidazole derivatives were reported to be versatile iNOS inhibitors by interacting with both dimer and monomer entities of the iNOS enzyme (30). On the other hand, active compounds from nitrite assay may affect enzymatic activity by directly binding to the active enzyme site (substratebinding site).…”

Section: Discussionmentioning

confidence: 99%