• Iron Chelator Ciclopirox In Congenital Erythropoietic Porphyria

    From ironjustice@21:1/5 to All on Mon Jan 14 14:55:50 2019
    Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria
    Pedro Urquiza1, Ana Laín1, Arantza Sanz-Parra1, Jorge Moreno2, Ganeko Bernardo-Seisdedos3, Pierre Dubus4,5, Esperanza González6, Virginia Gutiérrez-de-Juan7, Sandra García3, Hasier Eraña3, Itxaso San Juan1, Iratxe Macías1, Fredj Ben Bdira1,8, Paula
    Pluta1, Gabriel Ortega1,9, Julen Oyarzábal10, Rosario González-Muñiz11, Juan Rodríguez-Cuesta12, Juan Anguita12,13,14, Emilio Díez3, Jean-Marc Blouin15, Hubert de Verneuil15, José M. Mato7,16, Emmanuel Richard15, Juan M. Falcón-Pérez6,13,16,
    Joaquín Castilla2,13 and Oscar Millet1,*
    See all authors and affiliations

    Science Translational Medicine 19 Sep 2018:
    Vol. 10, Issue 459, eaat7467
    DOI: 10.1126/scitranslmed.aat7467

    Drug repurposing helps iron out porphyria
    Porphyria is an inherited incurable disorder resulting from the buildup of heme precursors throughout the body. Urquiza et al. showed that ciclopirox, already approved as an antifungal, allosterically stabilized a mutated biosynthetic enzyme (
    uroporphyrinogen III synthase or UROIIIS) that leads to this condition. Oral ciclopirox administration increased UROIIIS activity and reduced clinical symptoms in a mouse model of porphyria. Further work will be needed to show whether ciclopirox is
    suitable for chronic treatment. The authors’ drug repurposing pipeline could potentially be co-opted to investigate therapies for other enzyme mutations that cause metabolic disease.

    Abstract
    Congenital erythropoietic porphyria is a rare autosomal recessive disease produced by deficient activity of uroporphyrinogen III synthase, the fourth enzyme in the heme biosynthetic pathway. The disease affects many organs, can be life-threatening, and
    currently lacks curative treatments. Inherited mutations most commonly reduce the enzyme’s stability, altering its homeostasis and ultimately blunting intracellular heme production. This results in uroporphyrin by-product accumulation in the body,
    aggravating associated pathological symptoms such as skin photosensitivity and disfiguring phototoxic cutaneous lesions. We demonstrated that the synthetic marketed antifungal ciclopirox binds to the enzyme, stabilizing it. Ciclopirox targeted the enzyme
    at an allosteric site distant from the active center and did not affect the enzyme’s catalytic role. The drug restored enzymatic activity in vitro and ex vivo and was able to alleviate most clinical symptoms of congenital erythropoietic porphyria in a
    genetic mouse model of the disease at subtoxic concentrations. Our findings establish a possible line of therapeutic intervention against congenital erythropoietic porphyria, which is potentially applicable to most of deleterious missense mutations
    causing this devastating disease.

    Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

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    Repositioning the old fungicide ciclopirox for new medical uses.
    Shen T, Huang S1.
    Curr Pharm Des. 2016 May 30.
    Abstract
    BACKGROUND:
    Ciclopirox (CPX) has been used as an antifungal agent in various formulations to treat superficial fungal infection for decades. Its effectiveness and safety in treatments have been demonstrated by multiple studies.

    METHODS:
    Here we briefly summarize the pharmacological and toxicological properties of CPX as an antifungal agent, the new medical uses of CPX, as well as the correspondent molecular mechanisms.

    RESULTS:
    Increasing evidence has demonstrated that CPX is able to inhibit tumor growth, ameliorate diabetes and its complications, prevent human immunodeficiency virus (HIV) infection, and improve age-associated cardiovascular defects. Interestingly, its
    antifungal activity and all those newly observed effects are more or less related to its capability of chelating iron and interfering with the related signaling pathways. Mechanistically, CPX is capable of modulating the activities of certain enzymes or
    signaling pathways, such as ribonucleotide reductase (RR), deoxyhypusine hydroxylase (DOHH)/eukaryotic translation initiation factor 5A (eIF5A), Wnt/β-catenin, hypoxia-inducible factor-1α (HIF-1 α)/vascular endothelial growth factor (VEGF), vascular
    endothelial growth factor receptor 3 (VEGFR-3)/extracellular signal-regulated protein kinases 1/2, mammalian target of rapamycin, and cyclin dependent kinases (CDKs). Most of these activities are related to its chelation of iron.

    CONCLUSION:
    CPX, as an antifungal agent, may be repositioned for treatment of cancer and other human diseases.

    PMID: 27238364

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