Pharmacological chaperone

A pharmacological chaperone is a relatively new concept in the treatment of certain genetic disease. Small molecules which stabilize the correct folding of a protein are administered to the patient which results in a recovery of function lost due to mutation. Pharmacological chaperones present an attractive alternative to transplantation due its low risk and an alternative to enzyme replacement therapy due to lowered expense and oral availability. The development of these drugs has become possible as a result of our improved understanding of cell biology.

Targets for the pharmacological chaperoning must have a mutation which renders the protein unstable but not inactive. Pharmacological chaperones are particularly effective if a small amount of the protein can make a big difference in terms of palliating the negative effects of the mutation.

All pharmacological chaperones so far have targeted proteins along the secretory pathway; this is because the function of the mutated enzymes is sequestered from the location of its synthesis. The following sequence describes the general technique for this set of proteins:

The mutated protein is unstable (in the thermodynamic sense) and in retrotranslocation to the cytoplasm is degraded by the proteasome. The pharmacological chaperone intercepts the mutated protein and stabilizes its fold, evading the retrotranslocation machinery. The protein can then be shuttled to its target destination (usually beyond the ER), where it performs its appropriate function.

Ironically, most pharmacological chaperones are inhibitors of the enzyme targeted; due to differing conditions in the target's destination (pH, metal ions, etc) the inhibitor is ejected, and the enzyme functions; or, the relatively high concentration of substrate outcompetes the inhibitor; or a combination of both effects enables the enzyme to function. Even if the chaperone continued to inhibit, for most of these diseases an inhibited amount of enzyme would be much better than quantitative degradation.