Bromocriptine as a Novel Pharmacological Chaperone for Mucopolysaccharidosis IV A

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.

Bromocriptine therapy: Review of mechanism of action, safety and tolerability

“…It is an autosomal recessive disease initiated by mutations in the gene encoding for the N‐acetylgalactosamine‐6‐sulfate sulfatase (GALNS) enzyme, therefore, causing lysosomal accumulation of chondroitin‐6‐sulfate and keratan sulfate 342–344 . Bromocriptine exert its effects by increasing the activity of GALNS and reducing lysosomal mass in fibroblasts in a mutation‐dependent manner 341 …”

“…Bromocriptine has been revealed to decrease autoantibodies production and modify the expression of surface molecules and most likely downregulates autoimmune phenomena via induction of natural non-specific CD8 suppressor cells. 324,[336][337][338][339][340] 3.9 | Bromocriptine in MPS IVA/Morquio A disease Recently, bromocriptine has been experimented in vitro as a potential therapy for MPS IVA/Morquio A disease, 341 which is a lysosomal storage disease in which the lysosomal enzymes lose the ability to appropriately breakdown mucopolysaccharides, leading to build-up sugar in blood, cells and connective tissues causing vast variety of symptoms, such as severe skeletal abnormalities, heart valve disease, corneal clouding, hearing loss and other impairments. It is an autosomal recessive disease initiated by mutations in the gene encoding for the Nacetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme, therefore, causing lysosomal accumulation of chondroitin-6-sulfate and keratan sulfate.…”

“…[342][343][344] Bromocriptine exert its effects by increasing the activity of GALNS and reducing lysosomal mass in fibroblasts in a mutation-dependent manner. 341…”

“…282,296 304,308 310 The therapeutic role of bromocriptine has been tried to verify successfully by various clinical trials conducted in different times for the management of PPCM, 102,104 adenomas, 124 mastalgia, 142,143 BPH, 152 and various autoimmune diseases. 331,335,340,376,377 Additionally, in vitro testing and computer aided studies have indicated the importance of bromocriptine for MPS IVA, 341 Chagas disease 353 and COVID-19. 369,370 However, until more absolute information and evidences become available, it would be considered as an experimental drug (apart from FDA-approved indication), and further clinical evaluations are needed before its implementation.…”

Molecular characterization of mucopolysaccharidosis type IVA patients in the Andean region of Colombia

“…Molecular docking was performed as previously described (Alméciga-Diaz et al, 2019;Olarte-Avellaneda et al, 2020). Briefly, the crystallographic structure of human GALNS (PDB: 4FDI) was prepared using YASARA View v11.4.18.…”