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

• Published in: Journal of medicinal chemistry 2019-07, Vol.62 (13), p.6175-6189
• Main Authors: Alméciga-Diaz, Carlos J, Hidalgo, Oscar A, Olarte-Avellaneda, Sergio, Rodríguez-López, Alexander, Guzman, Esteban, Garzón, Rafael, Pimentel-Vera, Luisa Natalia, Puentes-Tellez, María Alejandra, Rojas-Rodriguez, Andrés Felipe, Gorshkov, Kirill, Li, Rong, Zheng, Wei
• Format: Article
• Language: English
• Subjects: Catalytic Domain; Chondroitinsulfatases - antagonists & inhibitors; Chondroitinsulfatases - genetics; Chondroitinsulfatases - metabolism; Chromones - metabolism; Chromones - pharmacology; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Ezetimibe - metabolism; Ezetimibe - pharmacology; Fibroblasts - metabolism; HEK293 Cells; Humans; Lysosomes - metabolism; Microtubule-Associated Proteins - metabolism; Molecular Docking Simulation; Molecular Dynamics Simulation; Mucopolysaccharidosis IV - drug therapy; Pichia - genetics; Protein Binding - drug effects; Protein Stability - drug effects; Rare Diseases - drug therapy; Recombinant Proteins - metabolism; RNA-Binding Proteins - metabolism
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b00428

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.