A number of studies published in the last several years have described the use of a group of low-molecular-weight compounds to reverse the mislocalization and/or aggregation of proteins associated with human disease. These compounds that include polyols such as glycerol, trimethylamines such as trimethylamine N-oxide (TMAO) and amino acid derivatives have been called “chemical chaperones.” Recent studies have suggested that other compounds, such as 4-phenylbutyric acid (PBA) and membrane-permeable forms of enzyme antagonists, ligands or even substrates, can also act as chemical chaperones for misfolded or mislocalized enzymes. The mechanisms by which chemical chaperones function are not fully understood but are thought to include stabilization of improperly folded proteins, reduction of aggregation, prevention of nonproductive interactions with other resident proteins and alteration of the activity of endogenous chaperones in such a way that the affected proteins are more efficiently transported to the appropriate intracellular or extracellular destination (Fig. 1). Chemical chaperones of the glycerol, TMAO and PBA class have general effects on multiple proteins while antagonists, ligands and substrates are thought to affect only the specific proteins with which they interact.

In addition to having the versatility of general or specific effects, the use of the chemical chaperone strategy is theoretically attractive because of its applicability to a wide range of pathologic conditions. Abnormal localization and/or aggregation of protein has become recognized as a critical issue in a growing number of inherited diseases, including cystic fibrosis,