Potent inhibition of respiratory syncytial virus by combination treatment with 2-5A antisense and ribavirin.
Potent inhibition of respiratory syncytial virus by combination treatment with 2-5A antisense and ribavirin.
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2-5A 反义药物和利巴韦林联合治疗可有效抑制呼吸道合胞病毒。
DOI：
10.1016/j.antiviral.2003.10.005
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Chaudhary,Nilabh
中科院分区：
文献类型：
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作者：
Xu,Zan;Kuang,Mei;Okicki,JamesR;Cramer,Hagen;Chaudhary,Nilabh
呼吸道合胞病毒（RSV）是婴幼儿和老年人下呼吸道疾病的主要原因。利巴韦林是美国目前唯一批准用于治疗RSV感染的药物，需要高剂量才有效因此，它在治疗RSV感染方面的临床疗效有限。已经显示，细胞核糖核酸酶RNase L可以被连接到与RSV基因组互补的反义序列的2′-5′连接的四腺苷酸（2-5A）募集，以特异性切割RSV基因组RNA。在这里，我们通过使用几种不同的病毒测定证实了先导2-5A反义化合物RBI 034的抗病毒活性。我们证明RBI 034在抑制RSV复制方面比缺乏2-5A的反义或小干扰dsRNA（siRNA）更有效。尽管在RSV感染的共同治疗中观察到RBI 034的最佳抗病毒活性，但即使在感染开始后24小时施用时，其仍然有效。有趣的是，RBI 034的活性可以通过与利巴韦林的组合治疗进一步增强。在次优浓度下，利巴韦林和RBI 034均不能有效抑制RSV复制。然而，这两种药物在相同的次优浓度下的组合显示出有效的抑制活性。在原代人气道上皮细胞中也证实了联合治疗对RSV复制的有效减少。因此，2-5A反义化合物RBI 034和利巴韦林的组合疗法可能是比单独利巴韦林更有效的治疗RSV感染的治疗方法。
Respiratory syncytial virus (RSV) is a major cause of lower respiratory diseases in infants, young children, and the elderly. Ribavirin, the only currently approved drug for the treatment of RSV infections in the U.S., requires high doses to be effective. Therefore, it has only a limited clinical efficacy in the treatment of RSV infections. It has been shown that a cellular ribonuclease, RNase L, can be recruited by 2′–5′ linked tetra-adenylates (2–5A) attached to an antisense sequence complementary to the RSV genome to specifically cleave RSV genomic RNA. Here we confirm the antiviral activity of the lead 2–5A antisense compound, RBI034, by using several different viral assays. We demonstrate that RBI034 is more efficient than antisense lacking 2–5A or small interfering dsRNA (siRNA) in inhibiting RSV replication. Although the best antiviral activity of RBI034 was observed with co-treatment of RSV infection, it remained effective even when administrated 24h after the initiation of infection. Interestingly, the activity of RBI034 can be further enhanced by a combination treatment with ribavirin. At suboptimal concentrations, neither ribavirin nor RBI034 was effective in suppressing RSV replication. However, a combination of these two drugs at the same suboptimal concentrations showed a potent inhibitory activity. The potent reduction of RSV replication by combination treatment was also confirmed in primary human airway epithelial cells. Therefore, a combination therapy of the 2–5A antisense compound RBI034 and ribavirin might be a more effective therapeutic approach for treating RSV infections than ribavirin alone.