Lassa virus (LASV) is the causative agent of Lassa hemorrhagic fever in humans, and the limited therapeutic treatment for Lassa fever poses significant threat to public health in West Africa. Using an HIV based pseudovirus platform, we identified isavuconazole, a triazole antifungal for systemic use, as a LASV entry inhibitor with an EC50 of 1.2 μM. Isavuconazole inhibits Lassa virus entry by blocking the pH dependent viral fusion mediated by the Lassa virus surface glycoprotein. Fragment replacement mutational study indicated that isavuconazole targets the stable signal peptide (SSP)-membrane fusion subunit (GP2) interface of Lassa glycoprotein. Further mutational study of the SSP-GP2 region of LASV glycoprotein revealed that S27 in the N-terminal transmembrane region of SSP and V431, F434 and V435 in the transmembrane domain of GP2 affect anti-LASV activity of isavuconazole. Isavuconazole also displays antiviral activity to five New World (NW) mammarenaviruses that cause hemorrhagic fever. This study facilitates the potential repurposing of isavuconazole for therapeutic intervention against human-pathogenic arenaviruses, and provides the basis for further structural optimization of arenavirus fusion inhibitors based on the predicted structural characteristics of the unique SSP-GP2 interface.

中文翻译：

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抗真菌药伊沙康康唑通过靶向lassa病毒糖蛋白的稳定信号肽-GP2亚基界面来抑制lassa病毒的进入。

拉沙病毒（LASV）是人类拉沙出血热的病原体，拉沙热的有限治疗方法对西非的公共卫生构成了重大威胁。使用基于HIV的伪病毒平台，我们确定了isavuconazole（一种全身使用的三唑类抗真菌药）是LASV进入抑制剂，EC50为1.2μM。Isavuconazole通过阻断由Lassa病毒表面糖蛋白介导的pH依赖性病毒融合来抑制Lassa病毒的进入。片段置换突变研究表明，伊沙康康唑靶向拉沙糖蛋白的稳定信号肽（SSP）-膜融合亚基（GP2）界面。对LASV糖蛋白的SSP-GP2区进行的进一步突变研究表明，SSP和V431的N端跨膜区中存在S27，GP2跨膜结构域中的F434和V435影响伊沙康康唑的抗LASV活性。Isavuconazole也对五种引起出血热的New World（NW）乳肾病毒显示抗病毒活性。这项研究促进了伊沙康康唑可能用于针对人类致病性鼻病毒的治疗干预，并为基于独特的SSP-GP2接口的预测结构特征的鼻病毒融合抑制剂的进一步结构优化提供了基础。