Caselmann W H, Eisenhardt S, Alt M
Department of General Internal Medicine, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany.
Intervirology. 1997;40(5-6):394-9. doi: 10.1159/000150571.
Antisense oligodeoxynucleotides (ODNS) can be used to specifically inhibit hepatitis C viral gene expression. Due to its high degree of conservation and its important function as internal ribosomal entry site, the 5'-non-coding region of the hepatitis C virus has been the most effective target to inhibit translation so far. Inhibition of luciferase reporter gene expression of up to 96 +/- 2% has been achieved. Modifications of ODNs like phosphorothioate, methylphosphonate or benzylphosphonate modification of terminal or intramolecular internucleotide phosphates lead to altered lipophilicity and binding stability to its RNA target and resistance against serum nucleases. The mode of action of ODNs is mainly dependent on an efficient induction of RNase H activity. The uptake of ODNs occurs via receptor-mediated or absorptive and fluid-phase endocytosis. After release from the endosomes, ODNs may exert their effects by interaction with cytosolic or nuclear structures. Side effects can occur when this interaction affects intra- or extracellular targets essential for biological cell function. If these problems can be solved, antisense technology has the potential for future therapy of human disease.
反义寡脱氧核苷酸（ODNs）可用于特异性抑制丙型肝炎病毒基因表达。由于丙型肝炎病毒5'-非编码区具有高度保守性且作为内部核糖体进入位点具有重要功能，因此它一直是迄今为止抑制翻译最有效的靶点。已实现对荧光素酶报告基因表达高达96±2%的抑制。对ODNs进行修饰，如对末端或分子内核苷酸磷酸进行硫代磷酸酯、甲基磷酸酯或苄基磷酸酯修饰，会导致其亲脂性改变以及与RNA靶点的结合稳定性改变，并增强对血清核酸酶的抗性。ODNs的作用模式主要依赖于对RNase H活性的有效诱导。ODNs通过受体介导或吸附及液相内吞作用摄取。从内体释放后，ODNs可通过与胞质或核结构相互作用发挥其效应。当这种相互作用影响生物细胞功能所必需的细胞内或细胞外靶点时，可能会出现副作用。如果这些问题能够得到解决，反义技术在人类疾病的未来治疗中具有潜力。
