Targeted therapy of respiratory syncytial virus by 2-5A antisense.
Targeted therapy of respiratory syncytial virus by 2-5A antisense.
复制标题
2-5A反义病毒靶向治疗呼吸道合胞病毒。
DOI：
10.1081/ncn-200061780
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Xu,Zan
中科院分区：
文献类型：
--
作者：
Cramer,Hagen;Okicki,JamesR;Kuang,Mei;Xu,Zan
呼吸道合胞病毒是婴儿、幼儿、免疫功能低下患者和老年人呼吸道疾病的主要原因。以前的工作表明，RNA酶L，干扰素系统的抗病毒酶，可以通过将四聚体2′-5′-连接的寡腺苷酸（2 5A）连接到与RSV基因组内重复基因间序列互补的反义寡核苷酸（2 5A反义）来招募切割RSV基因组RNA。RBI 034是2 - 5A抗RSV化合物的2′-O-甲基RNA修饰类似物，在细胞培养研究中发现其具有增强的抗病毒活性，同时还以RNase L·和序列特异性方式切割RSV基因组RNA。RBI 034在细胞培养中抑制RSV复制的效果比唯一批准用于RSV感染的药物利巴韦林好50至100倍。在这里，我们表明，2 5A反义化合物的活性可以进一步增强干扰素或利巴韦林的组合治疗。联合治疗产生的抗RSV活性比单独治疗更有效。我们还证明了RBI 034在三种不同物种中对RSV有效：小鼠、棉鼠和非洲绿色猴。
Respiratory syncytial virus is a leading cause of respiratory disease in infants, young children, immunocompromized patients, and the elderly. Previous work has shown that RNase L, an antiviral enzyme of the interferon system, can be recruited to cleave RSV genomic RNA by attaching tetrameric 2′-5′-linked oligoadenylates (2 5A) to an antisense oligonucleotide complementary to repetitive intergenic sequences within the RSV genome (2 5A antisense). RBI034, a 2′-O-methyl RNA-modified analogue of the 2 5A anti-RSV compound, was found to have enhanced antiviral activity in cell culture studies while also cleaving RSV genomic RNA in an RNase L· and sequence-specific manner. RBI034′s efficacy in suppressing RSV replication in cell culture is 50 to 100 times better than ribavirin, the only approved drug for RSV infection. Here we show that the activity of 2 5A antisense compound can be further enhanced by a combination treatment with interferon or ribavirin. The anti-RSV activity resulting from combination treatment is more potent than either treatment alone. We also demonstrate that RBI034 is effective against RSV in three different species: mice, cotton rats, and African green monkeys.