Loo Tip W, Clarke David M
Department of Medicine and Department of Biochemistry, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
Expert Rev Mol Med. 2007 Jun 28;9(16):1-18. doi: 10.1017/S1462399407000361.
Proteins that are exported from the cell, or targeted to the cell surface or other organelles, are synthesised and assembled in the endoplasmic reticulum and then delivered to their destinations. Point mutations - the most common cause of human genetic diseases - can inhibit folding and assembly of the protein in the endoplasmic reticulum. The unstable or partially folded mutant protein does not undergo trafficking and is usually rapidly degraded. A potential therapy for protein misfolding is to correct defective protein folding and trafficking using pharmacological chaperones. Pharmacological chaperones are substrates or modulators that appear to function by directly binding to the partially folded biosynthetic intermediate to stabilise the protein and allow it to complete the folding process to yield a functional protein. Initial clinical studies with pharmacological chaperones have successfully reduced clinical symptoms of disease. Therefore, pharmacological chaperones show great promise as a new class of therapeutic agents that can be specifically tailored for a particular genetic disease.
从细胞中输出、靶向至细胞表面或其他细胞器的蛋白质，在内质网中合成并组装，然后被运送至其目的地。点突变——人类遗传疾病最常见的病因——可抑制蛋白质在内质网中的折叠和组装。不稳定或部分折叠的突变蛋白不会进行运输，通常会迅速降解。蛋白质错误折叠的一种潜在治疗方法是使用药理伴侣来纠正有缺陷的蛋白质折叠和运输。药理伴侣是底物或调节剂，其作用似乎是通过直接结合部分折叠的生物合成中间体来稳定蛋白质，并使其完成折叠过程以产生功能性蛋白质。药理伴侣的初步临床研究已成功减轻了疾病的临床症状。因此，药理伴侣作为一类可针对特定遗传疾病进行专门定制的新型治疗药物，具有巨大的潜力。
