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Novel therapeutic strategies for the treatment of protein-misfolding diseases

Published online by Cambridge University Press:  28 June 2007

Jean-Christophe Rochet
Affiliation:
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, RHPH 410A, West Lafayette, IN 47907, USA. Tel: +1 765 494 1413; Fax: +1 765 494 1414; E-mail: rochet@pharmacy.purdue.edu

Abstract

Most proteins in the cell adopt a compact, globular fold that determines their stability and function. Partial protein unfolding under conditions of cellular stress results in the exposure of hydrophobic regions normally buried in the interior of the native structure. Interactions involving the exposed hydrophobic surfaces of misfolded protein conformers lead to the formation of toxic aggregates, including oligomers, protofibrils and amyloid fibrils. A significant number of human disorders (e.g. Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and type II diabetes) are characterised by protein misfolding and aggregation. Over the past five years, outstanding progress has been made in the development of therapeutic strategies targeting these diseases. Three promising approaches include: (1) inhibiting protein aggregation with peptides or small molecules identified via structure-based drug design or high-throughput screening; (2) interfering with post-translational modifications that stimulate protein misfolding and aggregation; and (3) upregulating molecular chaperones or aggregate-clearance mechanisms. Ultimately, drug combinations that capitalise on more than one therapeutic strategy will constitute the most effective treatment for patients with these devastating illnesses.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2007

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References

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Further reading, resources and contacts

The PubChem website is a useful link with information relating to the biological activities of small molecules. It includes a database of chemical structures and the results of NIH-funded high-throughput screens:

Uversky, V.N. and Fink, A.L. (2006) Protein Misfolding, Aggregation and Conformational Diseases: Part A: Protein Aggregation and Conformational Diseases, SpringerCrossRefGoogle Scholar
Sipe, J.D. (2005) Amyloid Proteins: The Beta Sheet Conformation and Disease, John Wiley & SonsGoogle Scholar
Smith, H.J., Simons, C. and Sewell, R.D.E. (2007) Protein Misfolding in Neurodegenerative Diseases: Mechanisms and Therapeutic Strategies, CRC PressGoogle Scholar
Estrada, L.D. and Soto, C. (2006) Inhibition of protein misfolding and aggregation by small rationally-designed peptides. Curr Pharm Des 12, 2557-2567CrossRefGoogle ScholarPubMed
Herbst, M. and Wanker, E.E. (2006) Therapeutic approaches to polyglutamine diseases: combating protein misfolding and aggregation. Curr Pharm Des 12, 2543-2555CrossRefGoogle ScholarPubMed
May, B.C., Govaerts, C. and Cohen, F.E. (2006) Developing therapeutics for the diseases of protein misfolding. Neurology 66, S118-122CrossRefGoogle ScholarPubMed
http://www.alz.org/ (Alzheimer's Association)Google Scholar
http://www.hdfoundation.org/ (Hereditary Disease Foundation)Google Scholar
http://www.apdaparkinson.org (American Parkinson Disease Association)Google Scholar
http://www.michaeljfox.org/ (Michael J. Fox Foundation)Google Scholar
http://www.parkinson.org (National Parkinson Foundation)Google Scholar
http://www.pdf.org/ (Parkinson's Disease Foundation)Google Scholar
Uversky, V.N. and Fink, A.L. (2006) Protein Misfolding, Aggregation and Conformational Diseases: Part A: Protein Aggregation and Conformational Diseases, SpringerCrossRefGoogle Scholar
Sipe, J.D. (2005) Amyloid Proteins: The Beta Sheet Conformation and Disease, John Wiley & SonsGoogle Scholar
Smith, H.J., Simons, C. and Sewell, R.D.E. (2007) Protein Misfolding in Neurodegenerative Diseases: Mechanisms and Therapeutic Strategies, CRC PressGoogle Scholar
Estrada, L.D. and Soto, C. (2006) Inhibition of protein misfolding and aggregation by small rationally-designed peptides. Curr Pharm Des 12, 2557-2567CrossRefGoogle ScholarPubMed
Herbst, M. and Wanker, E.E. (2006) Therapeutic approaches to polyglutamine diseases: combating protein misfolding and aggregation. Curr Pharm Des 12, 2543-2555CrossRefGoogle ScholarPubMed
May, B.C., Govaerts, C. and Cohen, F.E. (2006) Developing therapeutics for the diseases of protein misfolding. Neurology 66, S118-122CrossRefGoogle ScholarPubMed
http://www.alz.org/ (Alzheimer's Association)Google Scholar
http://www.hdfoundation.org/ (Hereditary Disease Foundation)Google Scholar
http://www.apdaparkinson.org (American Parkinson Disease Association)Google Scholar
http://www.michaeljfox.org/ (Michael J. Fox Foundation)Google Scholar
http://www.parkinson.org (National Parkinson Foundation)Google Scholar
http://www.pdf.org/ (Parkinson's Disease Foundation)Google Scholar