Chaperoned strategy

Chemical/pharmacological chaperone strategies aim at correcting this impaired folding through stabilization of the enzyme in its proper fold, which can be achieved by inhibition of the enzyme active site. The caveat of this strategy... 

Neither chemical nor pharmacological chaperones lead to wild-type expression levels of the mutant proteins at the cell surface. Alternative or additional strategies are needed to improve the intracellular transport of the mutant proteins. In the future, dtugs may also be developed that influence those components of the quality control system that are involed in the retention of misfolded proteins. 

This strategy is somewhat reminescent of the biological folding pathways of natural polypeptides that use selective interactions with effectors (Ca2+, chaperone proteins, etc.) to start the nucleation of the secondary structures [5] and has been used successfully to prepare well defined peptide nanostructures by several groups. 

Sawkar, A. R., Cheng, W. C., Beutler, E., Wong, C. H., Balch, W. E. and Kelly, J. W. (2002). Chemical chaperones increase the cellular activity of N370S beta-glucosidase A therapeutic strategy for Gaucher disease. Proc. Natl. Acad. Sci. USA 99, 15428-15433. 

Burrows JA, Willis LK, Perlmutter DH. Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z A potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Proc. Natl. Acad. Sci. U.S.A. 2000 97 1796-1801. 

Yu Z, Sawkar AR, Kelly JW. Pharmacologic chaperoning as a strategy to treat Gaucher disease. FEES J. 2007 274 4944-4950. 

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