Bespalov Maxim M, Saarma Mart
Institute of Biotechnology, University of Helsinki, Viikinkaari 9, PO Box 56, FIN-00014 Helsinki, Finland.
Trends Pharmacol Sci. 2007 Feb;28(2):68-74. doi: 10.1016/j.tips.2006.12.005. Epub 2007 Jan 10.
Glial-cell-line-derived neurotrophic factor (GDNF) family ligands (GFLs), which consist of GDNF, neurturin, artemin and persephin, regulate the development and maintenance of the nervous system. GDNF protects and repairs dopamine-containing neurons, which degenerate in Parkinson's disease, and motoneurons, which die in amyotrophic lateral sclerosis. GDNF and neurturin have shown promise in clinical trials of Parkinson's disease, and artemin is currently undergoing clinical trials for chronic pain treatment. However, the delivery of GFLs into the brain through invasive approaches such as neurosurgery, viral vectors or by the use of encapsulated cells is associated with multiple obstacles. The development of small molecules that specifically activate GFL receptors and that can be applied systemically would overcome most of these problems. The unique nature of the GFL receptors, recent progress in elucidation of the 3D structures of GFLs and GFL-receptor complexes and the use of high-throughput screening have resulted in the development of the first small molecules that mimic the effects of the different GFLs.
胶质细胞系源性神经营养因子（GDNF）家族配体（GFLs）由GDNF、神经营养素、Artemin和Persephin组成，可调节神经系统的发育和维持。GDNF可保护和修复帕金森病中退化的含多巴胺神经元以及肌萎缩侧索硬化症中死亡的运动神经元。GDNF和神经营养素在帕金森病临床试验中已显示出前景，Artemin目前正在进行慢性疼痛治疗的临床试验。然而，通过神经外科手术、病毒载体或使用包封细胞等侵入性方法将GFLs递送至大脑存在多种障碍。开发能够特异性激活GFL受体且可全身应用的小分子将克服这些问题中的大多数。GFL受体的独特性质、GFLs和GFL-受体复合物三维结构解析的最新进展以及高通量筛选的应用，已促成了首批模拟不同GFLs作用的小分子的开发。
