Journal article
Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria
Science translational medicine, v 10(459), 7467
19 Sep 2018
PMID: 30232228
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria
- Creators
- Pedro Urquiza - CIC bioGUNEAna Lain - CIC bioGUNEArantza Sanz-Parra - CIC bioGUNEJorge Moreno - CIC bioGUNEGaneko Bernardo-Seisdedos - Atlas Mol Pharma SL, Derio 48160, SpainPierre Dubus - Université de BordeauxEsperanza Gonzalez - CIC bioGUNEVirginia Gutierrez-de-Juan - CIC bioGUNESandra Garcia - Atlas Mol Pharma SL, Derio 48160, SpainHasier Erana - Atlas Mol Pharma SL, Derio 48160, SpainItxaso San Juan - CIC bioGUNEIratxe Macias - CIC bioGUNEFredj Ben Bdira - Leiden UniversityPaula Pluta - CIC bioGUNEGabriel Ortega - University of California, Santa BarbaraJulen Oyarzabal - Universidad de NavarraRosario Gonzalez-Muniz - Instituto de Química MédicaJuan Rodriguez-Cuesta - CIC bioGUNEJuan Anguita - IkerbasqueEmilio Diez - Atlas Mol Pharma SL, Derio 48160, SpainJean-Marc Blouin - Univ Bordeaux, Biotherapie Malad Genet Inflammatoires & Canc, U1035, F-33000 Bordeaux, FranceHubert de Verneuil - Université de BordeauxJose M. Mato - Instituto de Salud Carlos IIIEmmanuel Richard - Université de BordeauxJuan M. Falcon-Perez - IkerbasqueJoaquin Castilla - IkerbasqueOscar Millet - CIC bioGUNE
- Publication Details
- Science translational medicine, v 10(459), 7467
- Publisher
- Amer Assoc Advancement Science
- Number of pages
- 9
- Grant note
- Department of Industry, Tourism, and Trade of the Government of the Autonomous Community of the Basque Country (Elkartek BG2017) CTQ2015-68756-R / Ministerio de Economia e Investigacion
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000444967400003
- Scopus ID
- 2-s2.0-85053520724
- Other Identifier
- 991022197351004721
UN Sustainable Development Goals (SDGs)
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology
- Medicine, Research & Experimental