Pharmacological chaperone

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Pharmacological chaperones , also known as pharmacoperones , are organic compounds which, as reversible inhibitors, bind specifically to unfolded proteins and thereby shift the folding dynamics of the proteins towards their correct conformation and stabilize them.

description

Wrongly folded proteins are the cause of a multitude of diseases. Among the protein misfolding disease ( English protein misfolding diseases ), for example, include amyloidosis , cystic fibrosis , amyotrophic lateral sclerosis , phenylketonuria , Parkinson's and Alzheimer's disease . In the cells of the affected patient, the misfolded proteins are separated out in the endoplasmic reticulum as part of the protein quality control and broken down in the proteasome . The lack of these proteins, which take on important functions in the cells as enzymes , receptors or messenger substances , for example , leads to the corresponding clinical pictures. The causes of the protein misfoldings are complex. They range from gene mutations in exons that lead to changes in the amino acid sequence , i.e. the primary structure of the gene product , to errors in transcription or translation . These errors have a direct influence on the secondary and tertiary structure , or on the protein folding kinetics. Pharmacological chaperones can intervene in the protein folding process and have a positive effect on it. These are small molecules that serve as chemical folding aids. This shifts the folding dynamics of a protein towards its correct conformation and stabilizes it. With the correct tertiary structure, the protein quality control in the endoplasmic reticulum is "passed" and the protein can fulfill its function at its destination.

The chemical chaperones are to be distinguished from the pharmacological chaperones . Chemical chaperones have a non-specific effect on the protein structure. For example, they prevent protein aggregation of unfolded proteins by increasing their solubility . In contrast, the pharmacological chaperones bind specifically to unfolded proteins - ideally only to one type of protein - and stabilize the structure of the protein.

Natural chaperones are cell-specific proteins that support the folding process of newly synthesized proteins. In an overexpression accumulations can partially misfolded proteins occur as protein aggregates are called.

Examples

The structural formula of Migalastat
The structural formula of sapropterin

Sapropterin is approved for the treatment of phenylketonuria (PKU). The cause of the disease are mutations in the PAH gene, which codes for the enzyme phenylalanine hydroxylase . As a pharmacological chaperone, sapropterin stabilizes the folding of a number of mutation variants of phenylalanine hydroxylase. About 30 to 50% of PKU patients respond to saproterin. Sapropterin was approved as the first pharmacological chaperone in the United States in December 2007 and in the European Union in April 2009 .

The imino sugar 1-Deoxygalactonojirimycin (DGJ, international non- proprietary name Migalastat ) is a pharmacological chaperone. It is an analogue of the terminal galactose of Gb3 and a reversible inhibitor of α-galactosidase A. In a large number of preclinical experiments it has been shown that migalastat is able to increase the activity of mutated variants of α-galactosidase A. As a small molecule, Migalastat has a very broad biodistribution in the organism and can, for example, reach the central nervous system and cross the blood-brain barrier . In addition, it is available orally . Migalastat is currently in Phase III clinical trials for efficacy testing in patients with Fabry disease .

Pharmacological chaperones could also become a future treatment option for diseases using protein aggregates such as Alzheimer's disease.

further reading

Individual evidence

  1. ↑ G. Sposny: Pharmacoperone. In: Laborjournal . Issue 1, 2003.
  2. ↑ PM Conn, A. Ulloa-Aguirre et al. a .: G protein-coupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo. In: Pharmacological reviews . Volume 59, Number 3, September 2007, pp. 225-250, ISSN  0031-6997 . doi : 10.1124 / pr.59.3.2 . PMID 17878512 . (Review).
  3. ↑ a b D. Manstein: Research Report 2009. (PDF; 110 kB) Institute for Biophysical Chemistry, p. 33.
  4. ^ S. Ishii, HH Chang et al. a .: Preclinical efficacy and safety of 1-deoxygalactonojirimycin in mice for Fabry disease. In: Journal of pharmacology and experimental therapeutics . Volume 328, Number 3, March 2009, pp. 723-731, ISSN  1521-0103 . doi : 10.1124 / jpet.108.149054 . PMID 19106170 .
  5. ↑ R. Hamanaka, T. Shinohara et al. a .: Rescue of mutant alpha-galactosidase A in the endoplasmic reticulum by 1-deoxygalactonojirimycin leads to trafficking to lysosomes. In: Biochimica et biophysica acta . Volume 1782, Number 6, June 2008, pp. 408-413, ISSN  0006-3002 . doi : 10.1016 / j.bbadis.2008.03.001 . PMID 18381081 .
  6. ↑ S. Vogelbein: The quality control system in post-ER compartments of eukaryotic cells using the example of the vasopressin V2 receptor. Dissertation, FU Berlin 2009, p. 21.
  7. ↑ T. Arakawa, Y. Kita et al. a .: Aggregation suppression of proteins by arginine during thermal unfolding. In: Protein and peptide letters. Volume 13, Number 9, 2006, pp. 921-927, ISSN  0929-8665 . PMID 17100648 .
  8. ↑ SW Gersting, M. Staudigl u. a .: Activation of phenylalanine hydroxylase induces positive cooperativity toward the natural cofactor. In: The Journal of biological chemistry . Volume 285, Number 40, October 2010, pp. 30686-30697, ISSN  1083-351X . doi : 10.1074 / jbc.M110.124016 . PMID 20667834 . PMC 2945563 (free full text).
  9. ↑ B. Wick-Urban: Eating normally despite ketonuria. In: Pharmazeutische Zeitung Online 15, 2007.
  10. ↑ LMU Munich: Molecular Pediatrics - Genetic Diseases with Protein Folding. Retrieved October 14, 2011.
  11. ↑ N. Asano, S. Ishii et al. a .: In vitro inhibition and intracellular enhancement of lysosomal alpha-galactosidase A activity in Fabry lymphoblasts by 1-deoxygalactonojirimycin and its derivatives. In: European Journal of Biochemistry . Volume 267, Number 13, July 2000, pp. 4179-4186, ISSN  0014-2956 . PMID 10866822 .
  12. ↑ S. Biastoff, B. Dräger: Calystegines. In: GA Cordell (Ed.): The Alkaloids: Chemistry and Biology. P. 91. Limited preview in Google Book search
  13. ↑ G. Andreotti, MR Guarracino et al. a .: Prediction of the responsiveness to pharmacological chaperones: lysosomal human alpha-galactosidase, a case of study. In: Orphanet Journal of Rare Diseases. Volume 5, 2010, p. 36, ISSN  1750-1172 . doi : 10.1186 / 1750-1172-5-36 . PMID 21138548 . PMC 3016270 (free full text). ( Open Access ).
  14. ↑ R. Khanna, R. Soska et al. a .: The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease. In: Molecular therapy. Volume 18, Number 1, January 2010, pp. 23-33, ISSN  1525-0024 . doi : 10.1038 / mt.2009.220 . PMID 19773742 . PMC 2839206 (free full text).
  15. ↑ Clinical study (phase III): Study of the Effects of Oral AT1001 (Migalastat Hydrochloride) in Patients With Fabry Disease at Clinicaltrials.gov of the NIH
  16. ^ SK Dash: Future targeted disease modifying drugs for Alzheimer's disease. In: Recent patents on CNS drug discovery. Volume 6, Number 1, January 2011, pp. 65-76, ISSN  1574-8898 . PMID 21073430 . (Review).
  17. ↑ ADDF awards $ 210,300 to Amicus Therapeutics to evaluate PCs for treating Alzheimer's disease. In: news-medical.net of May 7, 2010