RSV604, a novel inhibitor of respiratory syncytial virus replication
RSV604, a novel inhibitor of respiratory syncytial virus replication
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DOI：
10.1128/aac.00211-07
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发表时间：
2007-09-01
影响因子：
4.9
通讯作者：
Powell, Kenneth L.
中科院分区：
文献类型：
--
作者：
Chapman, Joanna;Abbott, Elizabeth;Powell, Kenneth L.
呼吸道合胞病毒（RSV）是全球下呼吸道感染的最常见原因，但尚无有效的疫苗或抗病毒治疗。在这里，我们报告了 RSV604 的发现和初步开发，RSV604 是一种具有亚微摩尔抗 RSV 活性的新型苯二氮卓类药物。事实证明，它对 A 型和 B 型病毒的所有临床分离株均具有同等效力。该化合物在体外产生耐药性的比率较低。测序显示，耐药病毒的核衣壳蛋白发生了突变。这是抗 RSV 化合物的新作用机制。在三维人呼吸道上皮细胞模型中，RSV604在粘膜接种后能够从上皮的基底外侧有效地抑制病毒复制。 RSV604目前正处于II期临床试验阶段，是新型RSV抑制剂中的第一个，可能具有有效治疗RSV疾病的巨大潜力。
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections worldwide, yet no effective vaccine or antiviral treatment is available. Here we report the discovery and initial development of RSV604, a novel benzodiazepine with submicromolar anti-RSV activity. It proved to be equipotent against all clinical isolates tested of both the A and B subtypes of the virus. The compound has a low rate of in vitro resistance development. Sequencing revealed that the resistant virus had mutations within the nucleocapsid protein. This is a novel mechanism of action for anti-RSV compounds. In a three-dimensional human airway epithelial cell model, RSV604 was able to pass from the basolateral side of the epithelium effectively to inhibit virus replication after mucosal inoculation. RSV604, which is currently in phase II clinical trials, represents the first in a new class of RSV inhibitors and may have significant potential for the effective treatment of RSV disease.