title: Using pharmacological chaperones to restore proteostasis.
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.
authors.affiliation: Center for Proteomics and Bioinformatics and Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Ya-Juan
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Di
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address: tingwei.mu@case.edu.
authors.forename: Ting-Wei
authors.initials: TW
authors.lastname: Mu
mesh_terms: D000818:Animals; D055808:Drug Discovery; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D017510:Protein Folding / Q000187:drug effects*; D021381:Protein Transport / Q000187:drug effects*; D057165:Proteostasis Deficiencies / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*
chemical_list: D007473:Ion Channels; D043562:Receptors, G-Protein-Coupled
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)
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