Mendre Christiane, Mouillac Bernard
Universités Montpellier 1 et 2, 141, 34094 Montpellier Cedex 05, France.
Med Sci (Paris). 2010 Jun-Jul;26(6-7):627-35. doi: 10.1051/medsci/2010266-7627.
Many genetic and neurodegenerative diseases in humans result from protein misfolding and/or aggregation. These diseases are named conformational diseases. As a result, the misfolded non functional proteins are rejected and misrouted by the cellular quality control system, and cannot play their endogenous physiological roles. Specific compounds (ligands, substrates or inhibitors) known as pharmacological chaperones are able to bind and stabilize these misfolded proteins. Their interaction allows the target proteins to escape the quality control system and to be functionally rescued. These pharmacochaperones may possess different intrinsic activity: they can be antagonists (inhibitors), agonists (activators) or allosteric modulators of the target receptors, ionic channels or enzymes. Pharmacological chaperones have obviously a therapeutic potential to treat rare diseases like cystic fibrosis, retinitis pigmentosa, nephrogenic diabetes insipidus, Fabry disease, Gaucher disease, but also for cancers and more frequent and highly invalidant neurodegenerative disorders such as Alzheimer's disease or Parkinson's disease.
人类的许多遗传和神经退行性疾病是由蛋白质错误折叠和/或聚集引起的。这些疾病被称为构象疾病。因此，错误折叠的无功能蛋白质会被细胞质量控制系统排斥并错误导向，无法发挥其内在的生理作用。被称为药理伴侣的特定化合物（配体、底物或抑制剂）能够结合并稳定这些错误折叠的蛋白质。它们的相互作用使靶蛋白能够逃离质量控制系统并在功能上得到挽救。这些药理伴侣可能具有不同的内在活性：它们可以是靶受体、离子通道或酶的拮抗剂（抑制剂）、激动剂（激活剂）或变构调节剂。药理伴侣显然具有治疗罕见疾病的潜力，如囊性纤维化、色素性视网膜炎、肾性尿崩症、法布里病、戈谢病，也可用于癌症以及更常见且使人极度衰弱的神经退行性疾病，如阿尔茨海默病或帕金森病。
