Chemical/pharmacological chaperone

Insitu Monitoring of Active-Site-Directed GBA Chemical/Pharmacological Chaperones... 

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... 

A number of different low molecular weight compounds are known to stablize proteins in their native conformation and, therefore, may be effective in correcting of protein folding abnormalities in vivo. Relevant compounds are iV-acetyl-L-lysine, L-camitine, taurine, betaine, ectoine, and hydroxy-ectoine [4]. Some of these chemical chaperones and pharmacological chaperones are already used in clinical trials to combat protein folding diseases, such as cystic fibrosis. 

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. 

Alpha-1-antitrypsin mutations are associated with early-onset emphysema and liver disease that results in early death (50). The Z-variant of the disease is the most common and is present in over 95% of cases. This variant has been shown to be rescued in vitro by treatment with proteasome inhibitors (50). Several chemical and pharmacological chaperones have also been shown to correct the secretion of the mutant protein, which include the glucosidase inhibitor castanospermine, as well as the mannosidase inhibitors kifunensine (Fig. 2b)... 

Figure 2 Structures of selected chemical (a) and pharmacological (b) chaperones are shown.

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. 

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