Bromocriptine as a Novel Pharmacological Chaperone
for Mucopolysaccharidosis IV A
Posted on 2020-06-28 - 13:43
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.
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Olarte-Avellaneda, Sergio; Cepeda Del Castillo, Jacobo; Rojas-Rodriguez, Andrés Felipe; Sánchez, Oscar; Rodríguez-López, Alexander; Suárez García, Diego A.; et al. (2020). Bromocriptine as a Novel Pharmacological Chaperone
for Mucopolysaccharidosis IV A. ACS Publications. Collection. https://doi.org/10.1021/acsmedchemlett.0c00042
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AUTHORS (8)
SO
Sergio Olarte-Avellaneda
JC
Jacobo Cepeda Del Castillo
AR
Andrés Felipe Rojas-Rodriguez
OS
Oscar Sánchez
AR
Alexander Rodríguez-López
DS
Diego A. Suárez García
LP
Luz Mary Salazar Pulido
CA
Carlos J. Alméciga-Díaz