Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria
Pedro Urquiza, Ana Laín, Arantza Sanz-Parra, Jorge Moreno, Ganeko Bernardo-Seisdedos, Pierre Dubus, Esperanza González, Virginia Gutiérrez-de-Juan, Sandra García, Hasier Eraña, Itxaso San Juan, Iratxe Macías, Fredj Ben Bdira, Paula Pluta, Gabriel Ortega, Julen Oyarzábal, Rosario González-Muñiz, Juan Rodríguez-Cuesta, Juan Anguita, Emilio Díez, Jean-Marc Blouin, Hubert de Verneuil, José M Mato, Emmanuel Richard, Juan M Falcón-Pérez, Joaquín Castilla, Oscar Millet
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.
CITA DEL ARTÍCULO Sci Transl Med. 2018 Sep 19;10(459):eaat7467. doi: 10.1126/scitranslmed.aat7467.