Identification and characterization of pharmacological chaperones to correct enzyme deficiencies in lysosomal storage disorders.

摘要: Many human diseases result from mutations in specific genes. Once translated, the resulting aberrant proteins may be functionally competent and produced at near-normal levels. However, because of mutations, are recognized by quality control system endoplasmic reticulum not processed or trafficked correctly, ultimately leading to cellular dysfunction disease. Pharmacological chaperones (PCs) small molecules designed mitigate this problem selectively binding stabilizing their target protein, thus reducing premature degradation, facilitating intracellular trafficking, increasing activity. Partial complete restoration normal function PCs has been shown for numerous types mutant proteins, including secreted transcription factors, ion channels, G protein-coupled receptors, and, importantly, lysosomal enzymes. Collectively, storage disorders (LSDs) genetic genes that encode enzymes, a deficiency essential enzymatic activity accumulation respective substrate. To date, over 50 different LSDs have identified, several which treated clinically with enzyme replacement therapy substrate reduction therapy, although insufficiently some cases. Importantly, wide range vitro assays now available measure interaction stabilization PCs, as well subsequent increases levels function. The application these identification characterization candidate enzymes will discussed review. In addition, considerations successful vivo use development treat discussed.