Pharmacological Chaperone Therapy

INTRODUCTION Pharmacological chaperone therapy (PCT) is a developing area in the treatment of diseases characterized by misfolded proteins arising from a genetic mutation. Candidates for PCT are mutant proteins that are still able to perform their function to some degree. The mutant protein must also suffer from a folding defect that causes retention in the endoplasmic reticulum (ER). Genetic mutations can result in misfolded proteins that are retained and degraded in the endoplasmic reticulum-associated protein degradation pathway (ERAD). Degradation of the protein causes a protein deficiency; the mutant protein can help alleviate the deficiency if it can still perform its function to some degree. Pharmacological chaperones are small molecules that reversibly bind to the protein and correct the folding defect through a stabilization effect. PCT increases the amount of mutant protein that is correctly processed and transported instead of being degraded. The pharmacological chaperone dissociates after transport allowing the mutant protein to function. The folding of a protein into the native form is a complex process. The native folded form of the protein is a free energy minimum encoded by the amino acid sequence of the protein. Changes in the primary sequence can alter the forces associated with protein folding such as hydrogen bonding, electrostatic interactions, and hydrophobic packing. While some mutations result in little or no change, the loss of stabilizing interactions or the introduction of unfavorable interactions can lead to less stable conformations compared to the native conformation. The three-dimensional conformation of a protein is a crucial factor in determining its viability and function. Mutations in active sites and subunit interfaces can cause poor interactions with substrates and subunits. Unstable and misfolded proteins often have reduced or abolished activity relative to the native form. A protein with diminished function can still be a viable part of the cell; however, large quantities of misfolded proteins can cause adverse effects and stress responses through unwanted interactions such as aggregation. To prevent the detrimental effects of large quantities of misfolded proteins, molecular chaperone proteins in the endoplasmic reticulum recognize misfolded proteins and reroute them through ERAD before they can be processed and transported to their cellular locations. The severity of the structure change and instability affects the amount of protein that is rerouted to ERAD verses completing post-translational modifications and folding. The fraction of misfolded protein that evades degradation and is transported to the proper