Rabies, a viral zoonosis, is responsible for almost 59,000 deaths each year, despite the existence of an effective post-exposure prophylaxis. Indeed, rabies causes acute encephalomyelitis, with a case-fatality rate of 100 % after the onset of neurological clinical signs. Therefore, the development of therapies to inhibit the rabies virus (RABV) is crucial. Here, we identified, from a 30,000 compound library screening, phthalazinone derivative compounds as potent inhibitors of RABV infection and more broadly of and even infections. Combining experiments, structural modelling, docking and assays, we demonstrated that phthalazinone derivatives display a strong inhibition of lyssaviruses infection by acting directly on the replication complex of the virus, and with noticeable effects in delaying the onset of the clinical signs in our mouse model.

中文翻译：

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二氮杂萘酮衍生物抗狂犬病病毒的作用机制

尽管存在有效的暴露后预防措施，但狂犬病是一种病毒性人畜共患病，每年仍导致近 59,000 人死亡。事实上，狂犬病会引起急性脑脊髓炎，出现神经临床症状后病死率为 100%。因此，开发抑制狂犬病病毒（RABV）的疗法至关重要。在这里，我们从 30,000 个化合物库筛选中鉴定出二氮杂萘酮衍生化合物是 RABV 感染乃至更广泛的感染的有效抑制剂。结合实验、结构建模、对接和测定，我们证明二氮杂萘酮衍生物通过直接作用于病毒的复制复合物，对狂犬病病毒属病毒感染具有强烈的抑制作用，并且在我们的小鼠模型中延迟临床症状的出现具有显着的效果。