Antifungal Imidazoles Block Assembly of Inducible NO Synthase into an Active Dimer

Sennequier, Nicolas; Wolan, Dennis W.; Stuehr, Dennis J.

doi:10.1074/jbc.274.2.930

Cited by 87 publications

(83 citation statements)

References 73 publications

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“…The activity of such inhibitors (expressed as IC 50 or K i values) vary from low nanomolar [146,147] to micromolar concentration range [117,148,149]. Using sitedirected mutagenesis or methods of combinatorial chemistry it is possible to improve inhibitory activity of peptide IDs by optimizing their amino acid composition and sequence [117,139,147,150].…”

Section: Inhibitors Of Dimerizationmentioning

confidence: 99%

“…Using sitedirected mutagenesis or methods of combinatorial chemistry it is possible to improve inhibitory activity of peptide IDs by optimizing their amino acid composition and sequence [117,139,147,150]. The peptidomimetic molecules or small organic molecules were also recognized as IDs [117,148,151,152].…”

Section: Inhibitors Of Dimerizationmentioning

confidence: 99%

“…Thus it was found that the imidazole derivative, clotrimazole, induced dissociation of inducible nitric oxide synthase into subunits in the absence of L-arginine and tertahydrobiopterin, whereas other derivatives prevented dimerization only [148]. The fungal metabolite, tryprostatin A, induced reversible disruption of the cytoplasmic microtubule assembly of 3Y1 cells [149].…”

Section: Inhibitors Of Dimerizationmentioning

confidence: 99%

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Protein‐protein interactions as a target for drugs in proteomics

et al. 2003

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Protein-protein interactions play a central role in numerous processes in the cell and are one of the main fields of functional proteomics. This review highlights the methods of bioinformatics and functional proteomics of protein-protein interaction investigation. The structures and properties of contact surfaces, forces involved in protein-protein interactions, kinetic and thermodynamic parameters of these reactions were considered. The properties of protein contact surfaces depend on their functions. The contact surfaces of permanent complexes resemble domain contacts or the protein core and it is reasonable to consider such complex formation as a continuation of protein folding. Characteristics of contact surfaces of temporary protein complexes share some similarities with active sites of enzymes. The contact surfaces of the temporary protein complexes have unique structure and properties and they are more conservative in comparison with active site of enzymes. So they represent prospective targets for a new generation of drugs. During the last decade, numerous investigations were undertaken to find or design small molecules that block protein dimerization or protein(peptide)-receptor interaction, or, on the contrary, to induce protein dimerization.

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Section: Inhibitors Of Dimerizationmentioning

confidence: 99%

Section: Inhibitors Of Dimerizationmentioning

confidence: 99%

Section: Inhibitors Of Dimerizationmentioning

confidence: 99%

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Protein‐protein interactions as a target for drugs in proteomics

et al. 2003

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“…A major difficulty in the use of these compounds is their lack of specificity for the iNOS isoform. The heme ligands imidazole and imidazolecontaining antifungal compounds such as clotrimazole and miconazole are known inhibitors of heme-containing enzymes including iNOS (22). These compounds have been shown to inhibit iNOS dimerization by binding to its heme ligand.…”

Section: Effect Of Inos Dimerization Inhibitors On Cellular Inos Actimentioning

confidence: 99%

“…These compounds have been shown to inhibit iNOS dimerization by binding to its heme ligand. However, they have low affinity to NOS and lack specificity for the iNOS isoform (22)(23)(24). Recently, screening of an encoded combinatorial chemical library, designed based on a structurally related series of compounds of a pyrimidineimidazole core, resulted in the discovery of a class of allosteric high-affinity potent and selective iNOS inhibitors.…”

Section: Effect Of Inos Dimerization Inhibitors On Cellular Inos Actimentioning

confidence: 99%

Regulation of inducible nitric oxide synthase by rapid cellular turnover and cotranslational down-regulation by dimerization inhibitors

Kolodziejski

Koo

Eissa

2004

Proc. Natl. Acad. Sci. U.S.A.

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Overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of many disorders. iNOS is notably distinguished from constitutive NOSs by its production of large amounts of NO for a prolonged period; hence, it was termed the high-output NOS. Understanding how cells regulate iNOS is a prerequisite for strategies aimed at modulating NO synthesis. iNOS is thought to be regulated primarily at the transcriptional level in response to cytokines and inflammatory mediators. In this study, we report a posttranslational regulatory mechanism for control of iNOS expression through a rapid cellular rate of turnover. Unexpectedly, iNOS cellular half-life was found to be relatively short. In primary bronchial epithelial cells, iNOS half-life was 1.6 ؎ 0.3 h. A similar half-life was found for iNOS in several cell lines. This fast rate of turnover is in sharp contrast to that reported for the constitutive NOS isoforms. iNOS half-life was not affected by intracellular depletion of tetrahydrobiopterin, a critical cofactor required for iNOS activity. Further, iNOS monomers and dimers had a similar half-life. Importantly, we discovered a previously unrecognized cotranslational down-regulation mechanism by which the newly discovered pyrimidineimidazole-based allosteric dimerization inhibitors of iNOS lead to reduced iNOS expression. This study provides insights into the cellular posttranslational mechanisms of iNOS and has important implications for design of selective iNOS inhibitors and their use in therapeutic strategies.degradation ͉ proteasome ͉ half-life N itric oxide (NO) is an important signaling and cytotoxic molecule that is synthesized from L-arginine by isoforms of nitric oxide synthase (NOS) (1-3). As a signaling molecule, NO is produced by two constitutive calcium (Ca 2ϩ )-dependent isoforms, neuronal NOS and endothelial NOS (or NOSI and NOSIII, respectively). Ca 2ϩ -activated calmodulin binds to and transiently activates constitutive NOS dimers (3). Because of the transient nature of elevated Ca 2ϩ levels, these isoforms produce small amounts of NO for short periods of time. As an agent of inflammation and cell-mediated immunity, NO is produced by a Ca 2ϩ -independent cytokine-inducible NOS (iNOS or NOSII) that is widely expressed in diverse cell types under transcriptional regulation by inflammatory mediators (2, 4). Calmodulin is tightly bound to iNOS even at basal Ca 2ϩ levels; therefore, iNOS is notably distinguished from the constitutive isoforms by its prolonged production of a relatively large amount of NO (5). iNOS has been implicated in the pathogenesis of many diseases including Alzheimer's disease, tuberculosis, asthma, transplant rejection, stroke, glaucoma, inflammatory bowel disease, arthritis, and septic shock (6, 7). Such wide implication has produced a corresponding intense interest in understanding the regulation of NO synthesis by iNOS with the goal of developing therapeutic strategies aimed at selective modulation of iNOS activity (8). Understan...

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