*Molecular Chaperones*

Currently the therapeutic application of chemical chaperones and pharmacological chaperones is being used to rehabilitate misfolded proteins and restore mutant protein activity. Chemical chaperones are small-molecular-weight compounds that act as artificial chaperones to stabilize the native conformation of proteins. Chemical chaperones such as glycerol and trimethylamine N-oxide correct temperature-sensitive protein folding abnormalities in cystic fibrosis transmembrane regulator (CFTR, ΔF508), p53, viral oncogene protein pp60src, and ubiquitin activating enzyme E1. However, chemical chaperones have low specificity, which produces undesired e ffects, and the concentrations needed to increase protein function are so high that they are toxic to cells. Therefore, chemical chaperones are not generally used in clinical practice. On the other hand, much work has been done on pharmacological chaperones, which work at low concentrations and have high specificity [130]. This strategy has already proved e ffective in restoring mutant PAH activity in the form of sapropterin [131]. Pharmacological chaperones to treat Fabry disease and Pompe disease show increased enzyme activity and decreased substrate accumulation and are already in clinical trials [130]. Similar candidate molecules to stabilize PAH and FAH should be identified by using high-throughput screening of drug libraries and studying thermal protein stability. Chaperones could be one of the best candidates to manipulate because of their diverse role in protein folding, assembly, and stability. Pharmacological chaperones alone or in combination with members of the UPS system (such as DUBs and E3 ligases) could be a promising therapeutic strategy for rescuing enzyme function.
