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.

中文翻译：

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RSV604，呼吸道合胞病毒复制的新型抑制剂。

呼吸道合胞病毒（RSV）是全世界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方法。在这里，我们报告发现和初步开发RSV604，一种具有亚微摩尔抗RSV活性的新型苯并二氮杂。事实证明，它与所有测试过的病毒A和B亚型的临床分离株均具有同等效力。该化合物的体外抗药性发生率低。测序表明，抗性病毒在核衣壳蛋白内具有突变。这是抗RSV化合物的新型作用机理。在三维人呼吸道上皮细胞模型中，RSV604能够从上皮基底外侧通过，从而有效地抑制粘膜接种后的病毒复制。RSV604，