CIC bioGUNE
Published September 21, 2018 | Version v1
Journal article Open

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

Authors/Creators

  • 1. Protein Stability and Inherited Disease Laboratory, CIC bioGUNE, 48160 Derio, Spain
  • 2. Prion Research Laboratory, CIC bioGUNE, 48160 Derio, Spain. 3 Atlas Molecular Pharma S. L., 48160 Derio, Spain
  • 3. Atlas Molecular Pharma S. L., 48160 Derio, Spain
  • 4. Univerité de Bordeaux, Bordeaux Research in Translational Oncology, INSERM U1053, F-33000 Bordeaux, France; INSERM, Biothérapie des Maladies Génétiques, Inflammatoires et Cancers, U1035, Bordeaux, France
  • 5. Exosomes Laboratory, CIC bioGUNE, 48160 Derio, Spain
  • 6. Liver Metabolism Laboratory, CIC bioGUNE, 48160 Derio, Spain
  • 7. Protein Stability and Inherited Disease Laboratory, CIC bioGUNE, 48160 Derio, Spain; Department of Macromolecular Biochemistry, Leiden Institute of Chemistry, 2300 RA Leiden, Netherlands
  • 8. Protein Stability and Inherited Disease Laboratory, CIC bioGUNE, 48160 Derio, Spain; Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, CA 93106–9510, USA
  • 9. Small Molecule Discovery Platform, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain
  • 10. Instituto de Química Médica, IQM-CSIC, 28006 Madrid, Spain
  • 11. Animal Facility, CIC bioGUNE, 48160 Derio, Spain
  • 12. Animal Facility, CIC bioGUNE, 48160 Derio, Spain; Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain; Macrophage and Tick Vaccine Laboratory, CIC bioGUNE, 48160 Derio, Spain
  • 13. Université de Bordeaux, Biothérapie des Maladies Génétiques, Inflammatoires et Cancers, U1035, F-33000 Bordeaux, France
  • 14. Liver Metabolism Laboratory, CIC bioGUNE, 48160 Derio, Spain; CIBERehd-ISCiii, 28029 Madrid, Spain
  • 15. Exosomes Laboratory, CIC bioGUNE, 48160 Derio, Spain; Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain; CIBERehd-ISCiii, 28029 Madrid, Spain
  • 16. Prion Research Laboratory, CIC bioGUNE, 48160 Derio, Spain. 3 Atlas Molecular Pharma S. L., 48160 Derio, Spain; Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain

Description

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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Urquiza et al - 2018 - Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria.pdf

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