Seminar

Protein (in)stability and rare diseases: bridging the gap in porphyria

Oscar Millet, PhD

Congenital erythropoietic porphyria is a rare autosomal recessive disease produced by a deficient activity in uroporphyrinogen III synthase, the fourth enzyme of the haem biosynthetic pathway. The disease impacts many organs, can be life-threatening and currently lacks curative treatments. Biochemically, inherited mutations most frequently reduce enzyme´s stability, altering its homeostasis and ultimately blunting intracellular haem production. This results in uroporphyrin by-product accumulation in the body, aggravating the pathology with symptoms like skin photosensitivity and disfiguring phototoxic cutaneous lesions. In here, we demonstrate that the synthetic marketed antimicrobial ciclopirox associates to the enzyme and stabilizes it. Ciclopirox targets the enzyme in an allosteric site distant from the active centre, not affecting the enzyme´s catalytic role. The drug restores the activity in vitro, in cellula and ex vivo, and is able to alleviate most of the clinical signs in a bona fide mouse model of the disease at sub-toxic concentrations, establishing a novel therapeutic intervention line against congenital erythropoietic porphyria, applicable to the majority of the deleterious missense mutations causing this devastating disease.