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Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

2015, Number 1

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Rev Invest Clin 2015; 67 (1)

Pharmacoperones: Targeting Therapeutics Toward Diseases Caused by Protein Misfolding

Ulloa-Aguirre A, Zariñán T, Conn PM

Language: English
References: 11
Page: 15-19
PDF size: 320.76 Kb.


ABSTRACT

Pharmacoperones are hydrophobic molecule drugs that enter cells and serve as a molecular framework to cause misfolded mutant proteins to fold properly and adopt a stable conformation compatible with proper intracellular trafficking. Pharmacoperones have successfully been used experimentally to rescue function of some misfolded proteins (enzymes, receptors, channels) that lead to disease. Identification of pharmacoperones by high-throughput screens of drug libraries will likely provide new molecules that may be potentially useful to treat diseases caused by protein misfolding.


REFERENCES

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  2. Ulloa-Aguirre A, Janovick JA, Brothers SP, Conn PM. Pharmacologic rescue of conformationally-defective proteins: implications for the treatment of human disease. Traffic. 2004;5:821-37.

  3. Ulloa-Aguirre A, Zarinan T, Dias JA, Conn PM. Mutations in G protein-coupled receptors that impact receptor trafficking and reproductive function. Mol Cell Endocrinol. 2014;382:411-23.

  4. Ishii S, Chang HH, Kawasaki K, et al. Mutant alpha-galactosidase A enzymes identified in Fabry disease patients with residual enzyme activity: biochemical characterization and restoration of normal intracellular processing by 1-deoxygalactonojirimycin. Biochem J. 2007;406:285-95.

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  6. Conn PM, Ulloa-Aguirre A, Ito J, Janovick JA. G protein-coupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo. Pharmacol Rev. 2007;59:225-50.

  7. Bernier V, Morello JP, Zarruk A, et al. Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol. 2006;17:232-43.

  8. Conn PM, Ulloa-Aguirre A. Trafficking of G-protein-coupled receptors to the plasma membrane: insights for pharmacoperone drugs. Trends Endocrinol Metab. 2010;21:190-7.

  9. Janovick JA, Stewart MD, Jacob D, et al. Restoration of testis function in hypogonadotropic hypogonadal mice harboring a misfolded GnRHR mutant by pharmacoperone drug therapy. Proc Natl Acad Sci USA. 2013;110:21030-5.

  10. Conn PM, Smithson DC, Hodder PS, et al. Transitioning pharmacoperones to therapeutic use: in vivo proof-of-principle and design of high throughput screens. Pharmacol Res. 2014;83:38-51.

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