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Pharmacol Res. 2014 May;83:3-9. doi: 10.1016/j.phrs.2014.04.002. Epub 2014 Apr 18.

Using pharmacological chaperones to restore proteostasis.

Author information

1
Center for Proteomics and Bioinformatics and Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
2
Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
3
Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address: tingwei.mu@case.edu.

Abstract

Normal organismal physiology depends on the maintenance of proteostasis in each cellular compartment to achieve a delicate balance between protein synthesis, folding, trafficking, and degradation while minimizing misfolding and aggregation. Defective proteostasis leads to numerous protein misfolding diseases. Pharmacological chaperones are cell-permeant small molecules that promote the proper folding and trafficking of a protein via direct binding to that protein. They stabilize their target protein in a protein-pharmacological chaperone state, increasing the natively folded protein population that can effectively engage trafficking machinery for transport to the final destination for function. Here, as regards the application of pharmacological chaperones, we focus on their capability to promote the folding and trafficking of lysosomal enzymes, G protein coupled receptors (GPCRs), and ion channels, each of which is presently an important drug target. Pharmacological chaperones hold great promise as potential therapeutics to ameliorate a variety of protein misfolding diseases.

KEYWORDS:

Chaperone; E4031 (PubChem CID: 3185); ERAD; GABA (PubChem CID: 119); GPCR; Ion channel; Lysosomal storage disease; NN-DNJ (PubChem CID: 501640); Naltrexone (PubChem CID: 5360515); Nicotine (PubChem CID: 89594); Pharmacological chaperone; Protein misfolding disease; Proteostasis; SR121463 (PubChem CID: 9810773)

PMID:
24747662
PMCID:
PMC4070435
DOI:
10.1016/j.phrs.2014.04.002
[Indexed for MEDLINE]
Free PMC Article

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