Tuning protein folding in lysosomal storage diseases: the chemistry behind pharmacological chaperones

Pereira, David M.; Valentão, Patrı́cia

doi:10.1039/c7sc04712f

Cited by 72 publications

(62 citation statements)

References 84 publications

(101 reference statements)

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“…Agents that are at earlier developmental stages include N octylβ valienamine, a competitive inhibitor of βglucosidase, for Gaucher disease; N acetylcysteine for Pompe disease; α lobeline, 3,4,7trihydroxyisoflavone and azasugar in Krabbe disease; and N octyl4epi β valienamine and 5N,6S(N′butyliminomethylidene) 6thio1deoxygalactonojirimycin indicated in GM1 gangliosidosis 289 . The chemical structures of these pharmacological chaperones have been described recently 290,291 . Finally, an alternative strategy for stabiliz ing mutant enzymes, by binding away from the active site, is also being investigated.…”

Section: Substrate Reduction Therapies and Small-molecule Chaperonesmentioning

confidence: 99%

“…Further testing of NCGC607 in patients with PD and GBA mutations is awaited. Although promis ing, conflicting viewpoints still remain on the strength of such small molecule based approaches, primarily because these compounds bind to the catalytic site of enzymes, which may be a risk at high concentrations if they inhibit rather than increase activity 291,292 . More clinical trials are therefore required in order to analyse the robustness of this approach.…”

Section: Substrate Reduction Therapies and Small-molecule Chaperonesmentioning

confidence: 99%

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Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

498

374

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| Lysosomes are membrane-bound organelles with roles in processes involved in degrading and recycling cellular waste, cellular signalling and energy metabolism. Defects in genes encoding lysosomal proteins cause lysosomal storage disorders, in which enzyme replacement therapy has proved successful. Growing evidence also implicates roles for lysosomal dysfunction in more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. With a focus on lysosomal dysfunction in autoimmune disorders and neurodegenerative diseases -including lupus, rheumatoid arthritis, multiple sclerosis, Alzheimer disease and Parkinson disease -this Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs.

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Section: Substrate Reduction Therapies and Small-molecule Chaperonesmentioning

confidence: 99%

Section: Substrate Reduction Therapies and Small-molecule Chaperonesmentioning

confidence: 99%

Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

498

374

View full text Add to dashboard Cite

show abstract

“…Pathophysiological studies in different LSDs have suggested that in some cases, the amino acid change leads to loss of protein stability due to changes in their processing, folding, glycosylation, and pH stability, which promotes aggregation and can induce ER or Golgi apparatus retention and/or increased degradation, or defective transport to the lysosomes [37][38][39][40][41][42][43][44][45][46][47][48]. In this sense, the use of PCs as an alternative to restore the folding and trafficking of the mutated lysosomal proteins has been proposed [19,20]. It has been observed that PCs can increase the enzyme activity of the mutant proteins in a mutation-dependent manner, which may be sufficient to ameliorate most disease symptoms [49,50].…”

Section: Use Of Pharmacological Chaperones In Lsdsmentioning

confidence: 99%

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Diaz

Castillo

Rodríguez-López

et al. 2019

IJMS

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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.

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“…Pharmacological chaperones have ceased to be a niche category and have entered the clinical practice for some rare diseases caused primarily by protein instability. Many reviews exist to cover this subject with different points of view (a few examples [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]). We wanted to contribute by providing the readers with a list of research papers organized per disease that covers the years from 2000 to 2018.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations

Liguori

Monticelli

Allocca

et al. 2020

IJMS

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The term “pharmacological chaperone” was introduced 20 years ago. Since then the approach with this type of drug has been proposed for several diseases, lysosomal storage disorders representing the most popular targets. The hallmark of a pharmacological chaperone is its ability to bind a protein specifically and stabilize it. This property can be beneficial for curing diseases that are associated with protein mutants that are intrinsically active but unstable. The total activity of the affected proteins in the cell is lower than normal because they are cleared by the quality control system. Although most pharmacological chaperones are reversible competitive inhibitors or antagonists of their target proteins, the inhibitory activity is neither required nor desirable. This issue is well documented by specific examples among which those concerning Fabry disease. Direct specific binding is not the only mechanism by which small molecules can rescue mutant proteins in the cell. These drugs and the properly defined pharmacological chaperones can work together with different and possibly synergistic modes of action to revert a disease phenotype caused by an unstable protein.

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Tuning protein folding in lysosomal storage diseases: the chemistry behind pharmacological chaperones

Abstract: We review pharmacological chaperones used in lysosomal storage diseases, emphasizing medicinal chemistry approaches and mechanisms of action.

Cited by 72 publications

References 84 publications

Lysosomes as a therapeutic target

Lysosomes as a therapeutic target

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations

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