药物分子伴侣: 蛋白质折叠运输缺陷的新疗法

大量遗传性疾病的发生是由于基因突变引起蛋白质错误折叠而不能运输到作用位点，从而导致功能缺陷．近年来兴起的药物分子伴侣是恢复蛋白质折叠运输缺陷的新疗法，这类化合物一般为目的蛋白的底物类似物、受体配基或酶抑制剂等化学小分子，具细胞通透性，能在内质网中特异性识别并结合突变蛋白，校正并稳定其正确构象，协助其运输到正确位点，直接恢复突变蛋白功能，可治疗各种南蛋白质折叠运输缺陷导致的内分泌及代谢疾病．目前已报道的由药物分子伴侣恢复功能的突变蛋白主要为质膜蛋白及细胞器蛋白，如ATP结合盒转运蛋白、G-蛋白耦联受体及溶酶体酶等．大量的细胞及动物实验结果显示了药物分子伴侣的临床应用前景广阔，目前已有一例临床实验获得了成功．

Pharmacological Chaperones: Novel Therapeutic Strategies to Rescue Defective Protein Folding and Trafficking

Numerous inherited diseases are found to result from gene mutations that lead to mutant proteins, which can not fold correctly, fail to undergo trafficking, and are unable to reach their sites of action. Recently, pharmacological chaperones are developed as new therapeutics to rescue proteins defective in folding and trafficking. They are small cell-permeable chemicals, such as substrates, receptor ligands and enzyme inhibitors, which selectively recognize mutant proteins in the endoplasmic reticulum, correct their folding, stabilize the conformation, facilitate their trafficking to destination and yield functional proteins directly. Pharmacological chaperones represent promising avenues for the treatment of endocrine and metabolic diseases. They rescue a number of mutant proteins destined for the plasma membrane or organelles, such as ABC transporters, G-protein-coupled receptors, lysosomal enzymes and so on. Currently, one pharmacological chaperone has been successfully tested in clinical studies, and a lot of pharmacological chaperones have been tested and displayed positive results in cellular system and animal. This indicates that pharmacological chaperones will have great potential and broad prospects for clinical application in the future.