ml0c00042_si_001.pdf (1.01 MB)
Bromocriptine as a Novel Pharmacological Chaperone for Mucopolysaccharidosis IV A
journal contribution
posted on 2020-06-28, 13:43 authored by 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-DíazMucopolysaccharidosis
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.