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Therapeutic Approaches in Lysosomal Storage Diseases
 
 
Article

The New Pharmacological Chaperones PBXs Increase α-Galactosidase A Activity in Fabry Disease Cellular Models

1
Departamento de Química Orgánica, Universidade de Vigo, 36310 Vigo, Spain
2
BIOILS Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36312 Vigo, Spain
3
Rare Diseases and Pediatric Medicine Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36312 Vigo, Spain
4
Laboratory of Biomolecular Simulations, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
5
Department of Internal Medicine, University Hospital of A Coruña (CHUAC-SERGS), 15006 A Coruña, Spain
6
Department of Internal Medicine, Hospital de la Serranía, Ronda, 29400 Malaga, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Anna Rita Franco Migliaccio
Biomolecules 2021, 11(12), 1856; https://doi.org/10.3390/biom11121856
Received: 30 October 2021 / Revised: 4 December 2021 / Accepted: 7 December 2021 / Published: 10 December 2021
(This article belongs to the Special Issue Rare Diseases: From Molecular Pathways to Therapeutic Strategies)
Fabry disease is an X-linked multisystemic disorder caused by the impairment of lysosomal α-Galactosidase A, which leads to the progressive accumulation of glycosphingolipids and to defective lysosomal metabolism. Currently, Fabry disease is treated by enzyme replacement therapy or the orally administrated pharmacological chaperone Migalastat. Both therapeutic strategies present limitations, since enzyme replacement therapy has shown low half-life and bioavailability, while Migalastat is only approved for patients with specific mutations. The aim of this work was to assess the efficacy of PBX galactose analogues to stabilize α-Galactosidase A and therefore evaluate their potential use in Fabry patients with mutations that are not amenable to the treatment with Migalastat. We demonstrated that PBX compounds are safe and effective concerning stabilization of α-Galactosidase A in relevant cellular models of the disease, as assessed by enzymatic activity measurements, molecular modelling, and cell viability assays. This experimental evidence suggests that PBX compounds are promising candidates for the treatment of Fabry disease caused by mutations which affect the folding of α-Galactosidase A, even for GLA variants that are not amenable to the treatment with Migalastat. View Full-Text
Keywords: Fabry disease; pharmacological chaperones; GLA variants; Migalastat; lysosomal storage diseases Fabry disease; pharmacological chaperones; GLA variants; Migalastat; lysosomal storage diseases
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MDPI and ACS Style

Besada, P.; Gallardo-Gómez, M.; Pérez-Márquez, T.; Patiño-Álvarez, L.; Pantano, S.; Silva-López, C.; Terán, C.; Arévalo-Gómez, A.; Ruz-Zafra, A.; Fernández-Martín, J.; Ortolano, S. The New Pharmacological Chaperones PBXs Increase α-Galactosidase A Activity in Fabry Disease Cellular Models. Biomolecules 2021, 11, 1856. https://doi.org/10.3390/biom11121856

AMA Style

Besada P, Gallardo-Gómez M, Pérez-Márquez T, Patiño-Álvarez L, Pantano S, Silva-López C, Terán C, Arévalo-Gómez A, Ruz-Zafra A, Fernández-Martín J, Ortolano S. The New Pharmacological Chaperones PBXs Increase α-Galactosidase A Activity in Fabry Disease Cellular Models. Biomolecules. 2021; 11(12):1856. https://doi.org/10.3390/biom11121856

Chicago/Turabian Style

Besada, Pedro, María Gallardo-Gómez, Tania Pérez-Márquez, Lucía Patiño-Álvarez, Sergio Pantano, Carlos Silva-López, Carmen Terán, Ana Arévalo-Gómez, Aurora Ruz-Zafra, Julián Fernández-Martín, and Saida Ortolano. 2021. "The New Pharmacological Chaperones PBXs Increase α-Galactosidase A Activity in Fabry Disease Cellular Models" Biomolecules 11, no. 12: 1856. https://doi.org/10.3390/biom11121856

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