Bromocriptine as a Novel Pharmacological Chaperone for Mucopolysaccharidosis IV A

Sergio Olarte-Avellaneda; Jacobo Cepeda Del Castillo; Andrés Felipe Rojas-Rodriguez; Oscar Sánchez; Alexander Rodríguez-López; Diego A Suárez García; Luz Mary Salazar Pulido; Carlos J Alméciga-Díaz

doi:10.1021/acsmedchemlett.0c00042

Bromocriptine as a Novel Pharmacological Chaperone for Mucopolysaccharidosis IV A

ACS Med Chem Lett. 2020 Jun 24;11(7):1377-1385. doi: 10.1021/acsmedchemlett.0c00042. eCollection 2020 Jul 9.

Authors

Sergio Olarte-Avellaneda^{1

2}, Jacobo Cepeda Del Castillo¹, Andrés Felipe Rojas-Rodriguez³, Oscar Sánchez⁴, Alexander Rodríguez-López^{1

5}, Diego A Suárez García^{1

6}, Luz Mary Salazar Pulido⁷, Carlos J Alméciga-Díaz¹

Affiliations

¹ Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C. 110231, Colombia.
² Pharmacy Department, Faculty of Science, Universidad Nacional de Colombia, Bogotá D.C. 11001, Colombia.
³ Computational and Structural Biochemistry, Biochemistry and Nutrition Department, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C. 110231, Colombia.
⁴ Neurobiochemistry and Systems Physiology, Biochemistry and Nutrition Department, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C. 110231, Colombia.
⁵ Chemistry Department, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C. 110231, Colombia.
⁶ Faculty of Medicine, Universidad Nacional de Colombia, Bogotá D.C 11001, Colombia.
⁷ Chemistry Department, Faculty of Science, Universidad Nacional de Colombia, Bogotá D.C. 11001, Colombia.

Abstract

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the gene encoding for the enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS), leading to lysosomal accumulation of keratan sulfate (KS) and chondroitin-6-sulfate. In this study, we identified and characterized bromocriptine (BC) as a novel PC for MPS IVA. BC was identified through virtual screening and predicted to be docked within the active cavity of GALNS in a similar conformation to that observed for KS. BC interacted with similar residues to those predicted for natural GALNS substrates. In vitro inhibitory assay showed that BC at 50 μM reduced GALNS activity up to 30%. However, the activity of hrGALNS produced in HEK293 cells was increased up to 1.48-fold. BC increased GALNS activity and reduced lysosomal mass in MPS IVA fibroblasts in a mutation-dependent manner. Overall, these results show the potential of BC as a novel PC for MPS IVA and contribute to the consolidation of PCs as a potential therapy for this disease.