Safety

Compared to small molecule chemical chaperones, such as glycerol, DMSO, and TMAO, it is envisioned that specific pharmacological chaperones will have a safety advantage in the clinical setting. While both strategies are effective in promoting protein folding in the ER and subsequent trafficking through the secretory pathway m vitro, very high concentrations of chemical chaperones are typically required to see an effect, often too high to be practical at all. Furthermore, chemical chaperones act nonspecifically on many proteins, raising the possibility that they could lead to premature ER release of folding intermediates for many other normal proteins, some of which could lack stability and have a propensity for aggregation and toxicity in the post-ER environment [20]. Pharmacological chaperones, however, specifically target the protein of interest and are designed to elicit little to no global perturbation of the ER quality control system and the general protein folding environment. Because pharmacological chaperones specifically bind to their target proteins and can be selected to have suitably high affinity, lower concentrations may be sufficient to lead to therapeutic benefit, reducing or preventing off- t arget side effects (for review, see Reference 4).

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