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Chemical and pharmacological chaperones as new therapeutic agents

  • Tip W. Loo (a1) and David M. Clarke (a1)

Proteins that are exported from the cell, or targeted to the cell surface or other organelles, are synthesised and assembled in the endoplasmic reticulum and then delivered to their destinations. Point mutations – the most common cause of human genetic diseases – can inhibit folding and assembly of the protein in the endoplasmic reticulum. The unstable or partially folded mutant protein does not undergo trafficking and is usually rapidly degraded. A potential therapy for protein misfolding is to correct defective protein folding and trafficking using pharmacological chaperones. Pharmacological chaperones are substrates or modulators that appear to function by directly binding to the partially folded biosynthetic intermediate to stabilise the protein and allow it to complete the folding process to yield a functional protein. Initial clinical studies with pharmacological chaperones have successfully reduced clinical symptoms of disease. Therefore, pharmacological chaperones show great promise as a new class of therapeutic agents that can be specifically tailored for a particular genetic disease.

Corresponding author
*Corresponding author: David M. Clarke, Department of Medicine, University of Toronto, Rm 7342, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada. Tel/Fax: +1 416 978 1105; E-mail:
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The following papers describe in detail the mechanisms of protein misfolding and aggregation that are not discussed in this review. Other diseases involving protein misfolding and/or aggregations are also reviewed.

Sanders C.R. and Myers J.K. (2004) Disease-related misassembly of membrane proteins. Annu Rev Biophys Biomol Struct 33, 25-51
Arakawa T. et al. (2006) Small molecule pharmacological chaperones: from thermodynamic stabilization to pharmaceutical drugs. Biochim Biophys Acta 1764, 1677-1687
Gregersen N. et al. (2006) Protein misfolding and human disease. Annu Rev Genomics Hum Genet 7, 103-124
Rochet J-C. (2007) Novel therapeutic strategies for treatment of protein misfolding. Expert Rev Mol Med 9, 1-34
Smith A.J. et al. Molecular cell biology of KATP channels: implications for neonatal diabetes. Expert Rev Mol Med (in press)

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Expert Reviews in Molecular Medicine
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