Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Therapeutic approaches to protein-misfolding diseases

Abstract

Several sporadic and genetic diseases are caused by protein misfolding. These include cystic fibrosis and other devastating diseases of childhood as well as Alzheimer's, Parkinson's and other debilitating maladies of the elderly. A unified view of the molecular and cellular pathogenesis of these conditions has led to the search for chemical chaperones that can slow, arrest or revert disease progression. Molecules are now emerging that link our biophysical insights with our therapeutic aspirations.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Folding of mutant proteins destined to be lysosomal enzymes.

References

  1. Anfinsen, C. B. Principles that govern the folding of protein chains. Science 181, 223–230 (1973).

    ADS  CAS  Article  Google Scholar 

  2. Powell, K. & Zeitlin, P. L. Therapeutic approaches to repair defects in ΔF508 CFTR folding and cellular targeting. Adv. Drug Deliv. Rev. 54, 1395–1408 (2002).

    CAS  Article  Google Scholar 

  3. Howard, M. & Welch, W. J. Manipulating the folding pathway of ΔF508 CFTR using chemical chaperones. Methods Mol. Med. 70, 267–275 (2002).

    CAS  PubMed  Google Scholar 

  4. Carrell, R. W. & Lomas, D. A. Mechanisms of disease. Alpha1-antitrypsin deficiency—a model for conformational diseases. N. Engl. J. Med. 346, 45–53 (2002).

    CAS  Article  Google Scholar 

  5. Rochet, J.-C. & Lansbury, P. T. Jr. Amyloid fibrillogenesis: themes and variations. Curr. Opin. Struct. Biol. 10, 60–68 (2000).

    CAS  Article  Google Scholar 

  6. Kelly, J. W. Alternative conformations of amyloidogenic proteins govern their behavior. Curr. Opin. Struct. Biol. 6, 11–17 (1996).

    CAS  Article  Google Scholar 

  7. Fan, J.-Q. A contradictory treatment for lysosomal storage disorders: inhibitors enhance mutant enzyme activity. Trends Pharm. Sci. 24, 355–360 (2003).

    CAS  Article  Google Scholar 

  8. Sawkar, A. R. et al. Chemical chaperones increase the cellular activity of N370S β-glucosidase: a therapeutic strategy for Gaucher disease. Proc. Natl Acad. Sci. USA 99, 15428–15433 (2002).

    ADS  CAS  Article  Google Scholar 

  9. Morello, J.-P. et al. Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J. Clin. Inv. 105, 887–895 (2000).

    CAS  Article  Google Scholar 

  10. Petaja-Repo, U. E. et al. Ligands act as pharmacological chaperones and increase the efficiency of δ opioid receptor maturation. EMBO J. 21, 1628–1637 (2002).

    CAS  Article  Google Scholar 

  11. Janovick, J. A. et al. Structure–activity relations of successful pharmacologic chaperones for rescue of naturally occurring and manufactured mutants of the gonadotropin-releasing hormone receptor. J. Pharm. Exp. Ther. 305, 608–614 (2003).

    CAS  Article  Google Scholar 

  12. Noorwez, S. M. et al. Pharmacological chaperone-mediated in vivo folding and stabilization of the P23H-opsin mutant associated with autosomal dominant retinitis pigmentosa. J. Biol. Chem. 278, 14442–14450 (2003).

    CAS  Article  Google Scholar 

  13. Ficker, E., Obejero-Paz, C. A., Zhao, S. & Brown, A. M. The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations. J. Biol. Chem. 277, 4989–4998 (2002).

    CAS  Article  Google Scholar 

  14. Fan, J.-Q., Ishii, S., Asano, N. & Suzuki, Y. Accelerated transport and maturation of lysosomal α-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nature Med. 5, 112–115 (1999).

    CAS  Article  Google Scholar 

  15. Frustaci, A. et al. Improvement in cardiac function in the cardiac variant of Fabry's disease with galactose-infusion therapy. N. Engl. J. Med. 345, 25–32 (2001).

    CAS  Google Scholar 

  16. Springsteel, M. F. et al. Benzoflavone activators of the cystic fibrosis transmembrane conductance regulator: towards a pharmacophore model for the nucleotide-binding domain. Bioorg. Medic. Chem. 11, 4113–4120 (2003).

    CAS  Article  Google Scholar 

  17. Burrows, J. A. J., Willis, L. K. & Perlmutter, D. H. Chemical chaperones mediate increased secretion of mutant α1-antitrypsin (α1-AT) Z: a potential pharmacological strategy for prevention of liver injury and emphysema in α1-AT deficiency. Proc. Natl Acad. Sci. USA 97, 1796–1801 (2000).

    ADS  CAS  Article  Google Scholar 

  18. Hammarstrom, P., Jiang, X., Hurshman, A. R., Powers, E. T. & Kelly, J. W. Sequence-dependent denaturation energetics: a major determinant in amyloid disease diversity. Proc. Natl Acad. Sci. USA 99, 16427–16432 (2002).

    ADS  CAS  Article  Google Scholar 

  19. Hammarstrom, P., Wiseman, R. L., Powers, E. T. & Kelly, J. W. Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 299, 713–716 (2003).

    ADS  Article  Google Scholar 

  20. Schneider, F., Hammarstrom, P. & Kelly, J. W. Transthyretin slowly exchanges subunits under physiological conditions: a convenient chromatographic method to study subunit exchange in oligomeric proteins. Protein Sci. 10, 1606–1613 (2001).

    CAS  Article  Google Scholar 

  21. Nikolova, P. V., Wong, K.-B., DeDecker, B., Henckel, J. & Fersht, A. R. Mechanism of rescue of common p53 cancer mutations by second-site suppressor mutations. EMBO J. 19, 370–378 (2000).

    CAS  Article  Google Scholar 

  22. Sacchettini, J. C. & Kelly, J. W. Therapeutic strategies for human amyloid diseases. Nature Rev. Drug Discov. 1, 267–275 (2002).

    CAS  Article  Google Scholar 

  23. White, J. T. & Kelly, J. W. Support for the multigenic hypothesis of amyloidosis: the binding stoichiometry of retinol-binding protein, vitamin A, and thyroid hormone influences transthyretin amyloidogenicity in vitro. Proc. Natl Acad. Sci. USA 98, 13019–13024 (2001).

    ADS  CAS  Article  Google Scholar 

  24. Korth, C., May, B. C. H., Cohen, F. E. & Prusiner, S. B. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc. Natl Acad. Sci. USA 98, 9836–9841 (2001).

    ADS  CAS  Article  Google Scholar 

  25. May, B. C. H. et al. Potent inhibition of scrapie prion replication in cultured cells by bis-acridines. Proc. Natl Acad. Sci. USA 100, 3416–3421 (2003).

    ADS  CAS  Article  Google Scholar 

  26. Vogtherr, M. et al. Antimalarial drug quinacrine binds to C-terminal helix of cellular prion protein. J. Med. Chem. 46, 3563–3564 (2003).

    CAS  Article  Google Scholar 

  27. Peretz, D. et al. Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature 412, 739–743 (2001).

    ADS  CAS  Article  Google Scholar 

  28. White, A. R. et al. Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature 422, 80–83 (2003).

    ADS  CAS  Article  Google Scholar 

  29. Heppner, F. L. et al. Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies. Science 294, 178–182 (2001).

    ADS  CAS  Article  Google Scholar 

  30. Solomon, B. Anti-aggregating antibodies, a new approach towards treatment of conformational diseases. Curr. Med. Chem. 9, 1737–1749 (2002).

    CAS  Article  Google Scholar 

  31. Telling, G. C. et al. Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 83, 79–90 (1995).

    CAS  Article  Google Scholar 

  32. Ohno, S. et al. The antisense approach in amyloid light chain amyloidosis: identification of monoclonal Ig and inhibition of its production by antisense oligonucleotides in in vitro and in vivo models. J. Immunol. 169, 4039–4045 (2002).

    CAS  Article  Google Scholar 

  33. Findeis, M. A. Peptide inhibitors of beta amyloid aggregation. Curr. Top. Med. Chem. 2, 417–423 (2002).

    CAS  Article  Google Scholar 

  34. Yang, D.-S. et al. Assembly of Alzheimer's amyloid-β fibrils and approaches for therapeutic intervention. Amyloid 8, 10–19 (2001).

    CAS  PubMed  Google Scholar 

  35. Howlett, D. R. et al. Inhibition of fibril formation in β-amyloid peptide by a novel series of benzofurans. Biochem. J. 340, 283–289 (1999).

    CAS  Article  Google Scholar 

  36. Kelly, J. W. & Balch, W. E. Amyloid as a natural product. J. Cell Biol. 161, 461–462 (2003).

    CAS  Article  Google Scholar 

  37. Lamber, M. P. et al. Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc. Natl Acad. Sci. USA 95, 6448–6453 (1998).

    ADS  CAS  Article  Google Scholar 

  38. Kayed, R. et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300, 486–489 (2003).

    ADS  CAS  Article  Google Scholar 

  39. Walsh, D. M. et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002).

    ADS  CAS  Article  Google Scholar 

  40. Wolfe, M. S. γ-Secretase as a target for Alzheimer's disease. Curr. Top. Med. Chem. 2, 371–383 (2002).

    CAS  Article  Google Scholar 

  41. Vassar, R. β-Secretase (BACE) as a drug target for Alzheimer's disease. Adv. Drug Deliv. Rev. 54, 1589–1602 (2002).

    CAS  Article  Google Scholar 

  42. Jarrett, J. T. & Lansbury, P. T. Jr. Seeding 'one-dimensional crystallization' of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie? Cell 73, 1055–1058 (1993).

    CAS  Article  Google Scholar 

  43. Golde, T. E., Eriksen, J. L., Weggen, S., Sagi, S. A. & Koo, E. H. Nonsteroidal antiinflammatory drugs as therapeutic agents for Alzheimer's disease. Drug Dev. Res. 56, 415–420 (2002).

    CAS  Article  Google Scholar 

  44. Spooner, E. T., Desai, R. V., Mori, C., Leverone, J. F. & Lemere, C. A. The generation and characterization of potentially therapeutic Aβ antibodies in mice: differences according to strain and immunization protocol. Vaccine 21, 290–297 (2002).

    CAS  Article  Google Scholar 

  45. Nicoll, J. A. R. et al. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nature Med. 9, 448–452 (2003).

    CAS  Article  Google Scholar 

  46. Solomon, B. Protective molecules in Alzheimer's disease: therapeutic antibodies. Drug News Perspect. 15, 410–416 (2002).

    CAS  Article  Google Scholar 

  47. Colon, W. & Kelly, J. W. Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro. Biochemistry 31, 8654–8660 (1992).

    CAS  Article  Google Scholar 

  48. Fandrich, M., Fletcher, M. A. & Dobson, C. M. Amyloid fibrils from muscle myoglobin. Nature 410, 165–166 (2001).

    ADS  CAS  Article  Google Scholar 

  49. Baskakov, I. V., Legname, G., Prusiner, S. B. & Cohen, F. E. Folding of prion protein to its native α-helical conformation is under kinetic control. J. Biol. Chem. 276, 19687–19690 (2001).

    CAS  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cohen, F., Kelly, J. Therapeutic approaches to protein-misfolding diseases. Nature 426, 905–909 (2003). https://doi.org/10.1038/nature02265

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02265

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing