Olarte-Avellaneda, Sergio Cepeda Del Castillo, Jacobo Rojas-Rodriguez, Andrés Felipe Sánchez, Oscar Rodríguez-López, Alexander Suárez García, Diego A. Pulido, Luz Mary Salazar Alméciga-Díaz, Carlos J. Bromocriptine as a Novel Pharmacological Chaperone for Mucopolysaccharidosis IV A Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the gene encoding for the enzyme <i>N</i>-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. <i>In vitro</i> 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. acetylgalactosamine -6-sulfate sulf...;MPS IVA fibroblasts;Novel Pharmacological Chaperone;HEK 293 cells;KS;BC;MPS IVA;GALNS activity;lysosomal storage disease;50 μ M;novel PC 2020-06-28
    https://acs.figshare.com/articles/journal_contribution/Bromocriptine_as_a_Novel_Pharmacological_Chaperone_for_Mucopolysaccharidosis_IV_A/12579965
10.1021/acsmedchemlett.0c00042.s001