Trends in Endocrinology & Metabolism
Pharmacological chaperones: potential treatment for conformational diseases
Section snippets
Protein quality control systems
Numerous quality control mechanisms have evolved to protect living organisms against aberrant cellular activity. These systems are present to ensure that only completely and correctly folded proteins can reach their site of action. They require the participation of numerous accessory proteins known as molecular chaperones that, in addition to assisting protein folding, sense various ‘folding markers’ [9]. Proteins that are recognized as improperly or incompletely folded are generally targeted
Manipulating the quality control systems
The first evidence suggesting that the protein quality control systems could be manipulated came from studies carried out with the cystic fibrosis transmembrane conductance regulator (CFTR). Mutations of this chloride channel cause cystic fibrosis, a disease characterized by the inability of epithelial cells to secrete chloride, which leads to the production of thick and viscous mucus that causes severe functional obstruction of lungs and pancreas. One of these mutations, a deletion of a single
Chemical chaperones
From the above observations, the effects of low molecular weight compounds, such as the cellular osmolytes glycerol and trimethylamine N-oxide, in addition to deuterated water, previously shown to stabilize the native conformation of several proteins, were tested 13, 14. Consistent with the kinetic hypothesis proposed above, the three compounds increased the maturation of the mutant protein and rescued the cAMP-activated chloride conductance of cells expressing ΔF508 CFTR 13, 14. Although the
Early evidence and concept
The first indication that compounds selectively binding to intracellularly retained proteins could promote their proper folding and targeting came from work carried out on an energy-dependent transporter known as P-glycoprotein or multidrug resistance gene-1 product (MDR1). While characterizing synthetic mutations that resulted in ER retention and rapid degradation of the protein [15], Loo and Clarke found that treatments with substrates (vinblastine and capsaicin) or inhibitors (cyclosporin
Conclusion
The increasing number of examples showing that small molecules facilitate the folding and processing of proteins suggests that it might be a general phenomenon that could be applied to a large variety of proteins and conditions, thus having great potential therapeutic value.
Such small molecules can be divided into two classes: the chemical chaperones, which act as generic stabilizers of folding intermediates for all proteins, and the pharmacological chaperones, which show selectivity of action
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