Soreq H, Seidman S
Department of Biological Chemistry, Hebrew University, Jerusalem, Israel.
Isr Med Assoc J. 2000 Jul;2 Suppl:81-5.
The acetylcholine-hydrolyzing enzyme, acetylcholinesterase, is the molecular target of approved drugs for Alzheimer's disease and myasthenia gravis. However, recent data implicate AChE splicing variants in the etiology of complex diseases such as AD and MG. Despite the large arsenal of anti-AChE drugs, therapeutic inhibitors are primarily targeted towards an active site shared by all variants. In contrast, anti-sense oligonucleotides attack unique mRNA sequences rather than tertiary protein structures. AS-ODNs thus offer a means to target gene expression in a highly discriminative manner using very low concentrations of drug. In light of the likely role(s) of specific AChE variants in various diseases affecting cholinergic neurotransmission, the potential contribution that anti-sense technology can make towards improved approaches to anti-AChE therapeutics deserves serious attention.
乙酰胆碱水解酶，即乙酰胆碱酯酶，是治疗阿尔茨海默病和重症肌无力的已获批药物的分子靶点。然而，最近的数据表明，乙酰胆碱酯酶剪接变体与阿尔茨海默病和重症肌无力等复杂疾病的病因有关。尽管有大量的抗乙酰胆碱酯酶药物，但治疗性抑制剂主要针对所有变体共有的活性位点。相比之下，反义寡核苷酸攻击独特的mRNA序列而非蛋白质三级结构。因此，反义寡核苷酸提供了一种以高度特异性方式使用极低浓度药物来靶向基因表达的手段。鉴于特定的乙酰胆碱酯酶变体在影响胆碱能神经传递的各种疾病中可能发挥的作用，反义技术对改进抗乙酰胆碱酯酶治疗方法的潜在贡献值得认真关注。
