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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Jun 13

PMID 31188588

Citations 18

Authors

Carlos J Almeciga-Diaz

Oscar A Hidalgo

Sergio Olarte-Avellaneda

Alexander Rodriguez-Lopez

Esteban Guzman

Rafael Garzon

Luisa Natalia Pimentel-Vera

Maria Alejandra Puentes-Tellez

Andres Felipe Rojas-Rodriguez

Kirill Gorshkov

Rong Li

Wei Zheng

Affiliations

Soon will be listed here.

Abstract

Mucopolysaccharidosis type IVA (MPS IVA) is a rare disease caused by mutations in the gene encoding the lysosomal enzyme -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.

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