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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.

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  • Authors+Show Affiliations

    ,

    Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois. Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois.

    ,

    Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois. Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois.

    ,

    Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois. Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois.

    Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois. Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois.

    Source

    Medicinal research reviews : 2019 Jun 13 pg

    Pub Type(s)

    Journal Article
    Review

    Language

    eng

    PubMed ID

    31192483

    Citation

    Cinelli, Maris A., et al. "Inducible Nitric Oxide Synthase: Regulation, Structure, and Inhibition." Medicinal Research Reviews, 2019.
    Cinelli MA, Do HT, Miley GP, et al. Inducible nitric oxide synthase: Regulation, structure, and inhibition. Med Res Rev. 2019.
    Cinelli, M. A., Do, H. T., Miley, G. P., & Silverman, R. B. (2019). Inducible nitric oxide synthase: Regulation, structure, and inhibition. Medicinal Research Reviews, doi:10.1002/med.21599.
    Cinelli MA, et al. Inducible Nitric Oxide Synthase: Regulation, Structure, and Inhibition. Med Res Rev. 2019 Jun 13; PubMed PMID: 31192483.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Inducible nitric oxide synthase: Regulation, structure, and inhibition. AU - Cinelli,Maris A, AU - Do,Ha T, AU - Miley,Galen P, AU - Silverman,Richard B, Y1 - 2019/06/13/ PY - 2019/01/25/received PY - 2019/04/14/revised PY - 2019/05/13/accepted PY - 2019/6/14/entrez PY - 2019/6/14/pubmed PY - 2019/6/14/medline KW - animal models KW - cancer KW - enzyme inhibition KW - immune regulation KW - immune system activation KW - inducible nitric oxide synthase KW - inflammation KW - neurodegeneration KW - nitrergic signaling KW - nitric oxide KW - pain KW - reactive oxygen species KW - sepsis JF - Medicinal research reviews JO - Med Res Rev N2 - 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. SN - 1098-1128 UR - https://www.unboundmedicine.com/medline/citation/31192483/Inducible_nitric_oxide_synthase:_Regulation,_structure,_and_inhibition L2 - https://doi.org/10.1002/med.21599 DB - PRIME DP - Unbound Medicine ER -