Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria.

The off-patent marketed antifungal ciclopirox improves symptoms in a mouse model of congenital erythropoietic porphyria. 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. 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. [ABSTRACT FROM AUTHOR]