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, α1-antitrypsin (α1 AT) deficiency, Alzheimer's disease, prion diseases, familial Parkinsonism, familial forms of amyotrophic lateral sclerosis, spinocerebellar diseases, lysosomal storage diseases as well as in acquired ischemic diseases in which aggregated proteins may contribute to tissue injury (1). In addition to diseases in which abnormal folding may contribute to pathogenesis by a loss of function mechanism (loss of activity, loss of appropriate cellular localization), this strategy is being examined for diseases in which abnormal folding may contribute to pathogenesis by gain-of-function (cytotoxicity of aggregated proteins). Moreover, this strategy has been envisioned as a means for altering physiologic processes for therapeutic purposes, such as improving the efficiency by which antigen is presented by manipulating the assembly of antigenic peptides with MHC molecules. In this review, we will summarize the results of studies in which the chemical chaperone strategy has been tested in cell culture model systems, in experimental animals as well as in patients in vivo.

Because glycerol and other polyols were known to stabilize proteins against thermal denaturation (2–4) and to facilitate protein folding and oligomeric assembly (5–8), Sato et al. examined the effect of glycerol on the fate of mutant CFTRΔF508 (9). Because of its mutation, CFTRΔF508, the allele which characterizes ˜70% of all cystic fibrosis patients, is less efficient at reaching the apical plasma membrane of epithelial cells (10). Mutant CFTR molecules are retained in the ER in an immature state and are rapidly degraded by a process that involves the ubiquitin-dependent proteasomal system (11–13). The results of the Sato study showed that 10% glycerol (vol/vol) could mediate an increase in the transport of mutant CFTR molecules from the ER to the plasma membrane in a cell culture model system and this effect was associated with an increase in functional activity of CFTR (9). Most importantly, these studies suggested that the effect of glycerol was specific for the folding/maturation of mutant CFTR molecules and not a generalized effect on ER quality control mechanisms. Brown et al. showed that glycerol and two other low molecular weight organic compounds, deuterated water and TMAO, mediated increased posttranslational maturation of CFTRΔF508 in a cell culture model system and this was associated with increased chloride transport activity (14). Other studies have shown that chloride transport is increased significantly by the effect of DMSO (DMSO) on polarized epithelial cell lines expressing CFTRΔF508 (15). Specific amino acids also appear to affect maturation of CFTRΔF508 by a chaperone-like mechanism as evidenced by the effect of glutamine in a cell culture model system of CFTRΔF508 (16).

Log in or create a free account to read this content

Gain free access to this article, as well as selected content from this journal and more on nature.com

Access through your institution

or

Sign in or create an account
Continue with Google
Continue with ORCiD