Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

• Published in: International journal of molecular sciences Vol. 21; no. 1; p. 232
• Main Authors: Losada Díaz, Juan Camilo, Cepeda Del Castillo, Jacobo, Rodriguez-López, Edwin Alexander, Alméciga-Díaz, Carlos J
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29-12-2019; MDPI
• Subjects: Biological activity; Catabolism; Chaperones; Chemical bonds; Disease; Enzymes; FDA approval; Folding; Glycosaminoglycans; Glycosylation; Immunogenicity; Lysosomal storage diseases; Lysosomes; mucopolysaccharidoses; Mucopolysaccharidosis; Mutation; Oral administration; pharmacological chaperones; Pharmacology; Protein folding; Protein interaction; Protein transport; Review; small molecules; lysosomal storage diseases; pharmacological chaperones; mucopolysaccharidoses; small molecules
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21010232

The mucopolysaccharidoses (MPS) are a group of 11 lysosomal storage diseases (LSDs) produced by mutations in the enzymes involved in the lysosomal catabolism of glycosaminoglycans. Most of the mutations affecting these enzymes may lead to changes in processing, folding, glycosylation, pH stability, protein aggregation, and defective transport to the lysosomes. It this sense, it has been proposed that the use of small molecules, called pharmacological chaperones (PCs), can restore the folding, trafficking, and biological activity of mutated enzymes. PCs have the advantages of wide tissue distribution, potential oral administration, lower production cost, and fewer issues of immunogenicity than enzyme replacement therapy. In this paper, we will review the advances in the identification and characterization of PCs for the MPS. These molecules have been described for MPS II, IVA, and IVB, showing a mutation-dependent enhancement of the mutated enzymes. Although the results show the potential of this strategy, further studies should focus in the development of disease-specific cellular models that allow a proper screening and evaluation of PCs. In addition, in vivo evaluation, both pre-clinical and clinical, should be performed, before they can become a real therapeutic strategy for the treatment of MPS patients.