Identification of Ezetimibe and Pranlukast as Pharmacological Chaperones for the Treatment of the Rare Disease Mucopolysaccharidosis Type IVA

Mucopolysaccharidosis type IVA (MPS
IVA) is a rare disease caused
by mutations in the gene encoding the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). We report here
two GALNS pharmacological chaperones, ezetimibe and pranlukast, identified
by molecular docking-based virtual screening. These compounds bound
to the active cavity of GALNS and increased its thermal stability
as well as the production of recombinant GALNS in bacteria, yeast,
and HEK293 cells. MPS IVA fibroblasts treated with these chaperones
exhibited increases in GALNS protein and enzyme activity and reduced
the size of enlarged lysosomes. Abnormalities in autophagy markers
p62 and LC3B-II were alleviated by ezetimibe and pranlukast. Combined
treatment of recombinant GALNS with ezetimibe or pranlukast produced
an additive effect. Altogether, the results demonstrate that ezetimibe
and pranlukast can increase the yield of recombinant GALNS and be
used as a monotherapy or combination therapy to improve the therapeutic
efficacy of MPS IVA enzyme replacement therapy.