Pharmacological chaperones: potential treatment for conformational diseases

Bernier, Virginie; Lagacé, Monique; Bichet, Daniel G.; Bouvier, Michel

doi:10.1016/j.tem.2004.05.003

Cited by 254 publications

(246 citation statements)

References 53 publications

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“…loss or diminution of GnRH efficacy) by producing misfolded and misrouted receptors rather than by loss of the ability to bind ligand or couple to effector. Accordingly, 15 of the 17 HH-associated mutants can be rescued to some degree by pharmacological chaperones ("pharmacoperones"), small molecules (usually peptidomimetic antagonists) that enter cells and correct folding errors Bernier et al, 2004a;Bernier et al, 2004b). In the two remaining cases (hGnRHR(Ser 168 Arg) and hGnRHR(Ser 217 Arg)), thermodynamically unfavorable substitutions cause severe twisting of transmembrane segment 4 (TMS4) or TMS5, respectively, irreversibly preventing the alignment of extracellular loop 2 (ECL2) and the amino terminal, needed for proper positioning of amino acids Cys 14 and Cys 200 , a bridge which is requisite for creation of a properly folded human GnRHR that passes the cellular quality control system (Knollman et al, 2005;Janovick et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Janovick

Brothers

Cornea

et al. 2007

Molecular and Cellular Endocrinology

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SUMMARYAll reported GnRH receptor mutants (causing human hypogonadotropic hypogonadism) are misfolded proteins that cannot traffic to the plasma membrane. Pharmacoperones correct mis-folding and rescue mutants, routing them to the plasma membrane where they regain function. Because pharmacoperones are often peptidomimetic antagonists, these must be removed for receptor function after rescue; in vivo this necessitates pulsatile pharmacoperone administration. As an antecedent to in vivo studies, we determined whether pharmacoperones need to be present at the time of synthesis or whether previously misfolded proteins could be refolded and rescued. Accordingly, we blocked either protein synthesis or intra-cellular transport. Biochemical and morphological studies using 12 mutants and 10 pharmacoperones representing three different chemical classes show that previously synthesized mutant proteins, retained by the quality control system (QCS), are rescued by pharmacoperones, showing that pharmacoperone administration in vivo likely need not consider whether the target protein is being synthesized at the time of drug administration.

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Section: Introductionmentioning

confidence: 99%

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Janovick

Brothers

Cornea

et al. 2007

Molecular and Cellular Endocrinology

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“…Much like molecular chaperones they promote the folding of a range of proteins. A subset of the chemical chaperones is that of the pharmacological chaperones, which act with specificity for a particular protein and are frequently protein antagonists [15,[20][21][22].…”

Section: Molecular Chaperones and Er Quality Controlmentioning

confidence: 99%

“…Like other chemical chaperones they are small molecules capable of traversing the cell membrane and encouraging protein folding through non-covalent interactions [21]. Pharmacological chaperones can be protein ligands that bind the nascent protein or recover a late-folded mutant protein [28].…”

Section: Chemical Chaperone Applicationsmentioning

confidence: 99%

“…For instance, known chemical chaperones glycerol and trimethylamine-N-oxide (TMAO) were both found to restore activity of a mutant chloride channel in mice, yet effective serum concentrations were lethal in nearly half the mice [29]. Thus, because some chemical chaperones prove toxic in vivo, pharmacological chaperones are suggested to have great potential for human therapy [21]. Additionally, several authors have suggested that pharmacological chaperones effectiveness could further be improved through the application of multiple chaperones acting at different sites of the protein or along different parts of the protein folding or localization pathways [27,30].…”

Section: Chemical Chaperone Applicationsmentioning

confidence: 99%

“…One such strategy involves the use of chemical chaperones to augment the native action of molecular chaperones or recover specific misfolded proteins, prevent aggregation, and hence restore overall cell health. Indeed, studies have reported promising results regarding the use of chemical chaperones to treat disorders caused by protein misfolding [19][20][21]. In this review, we examine the evidence of ER stress, the role of chaperones, and the pharmacological potential of chaperone compounds for study in AMD.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Unfolding the therapeutic potential of chemical chaperones for age-related macular degeneration

Sauer

Patel

Chan

et al. 2008

Expert Review of Ophthalmology

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SUMMARYRecent studies suggest that pathological processes involved in age-related macular degeneration (AMD) might induce endoplasmic reticulum (ER) stress. Growing evidence demonstrates the ability of chemical chaperones to decrease ER stress and ameliorate ER stress-related disease phenotypes, suggesting that the field of chaperone therapy might hold novel treatments for AMD. In this review, we examine the evidence suggesting a role for ER stress in AMD. Furthermore, we discuss the use of chaperone therapy for the treatment of ER stress-associated diseases, including other neurodegenerative diseases and retinopathies. Finally, we examine strategies for identifying potential chaperone compounds and for experimentally demonstrating chaperone activity in in vitro and in vivo models of human disease.

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Overexpression of Membrane Proteins Using Pichia pastoris

et al. 2002

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Among the small number of expression systems validated for the mass production of eukaryotic membrane proteins (EMPs), the methylotrophic yeast Pichia pastoris stands as one of the most efficient hosts. This system has been used to produce crystallization-grade proteins for a variety of EMPs, from which high-resolution 3D structures have been determined. This unit describes a set of guidelines and instructions to overexpress membrane proteins using the P. pastoris system. Using a G protein-coupled receptor (GPCR) as a model EMP, these protocols illustrate the necessary steps, starting with the design of the DNA sequence to be expressed, through the preparation and analysis of samples containing the corresponding membrane protein of interest. In addition, recommendations are given on a series of experimental parameters that can be optimized to substantially improve the amount and/or the functionality of the expressed EMPs.

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Pharmacological chaperones: potential treatment for conformational diseases

Cited by 254 publications

References 53 publications

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Unfolding the therapeutic potential of chemical chaperones for age-related macular degeneration

Overexpression of Membrane Proteins Using Pichia pastoris

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