State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Antiviral Res. 2020 Feb;174:104701. doi: 10.1016/j.antiviral.2019.104701. Epub 2019 Dec 23.
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 EC 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.
拉沙病毒（LASV）是人类拉沙热的病原体，针对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。我们利用基于 HIV 的假病毒平台，鉴定出伊曲康唑（一种全身性三唑类抗真菌药物）是一种 LASV 进入抑制剂，其 EC 为 1.2 μM。伊曲康唑通过阻断拉沙病毒表面糖蛋白介导的 pH 依赖性病毒融合来抑制拉沙病毒进入。片段替换突变研究表明，伊曲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 SSP-GP2 区域的进一步突变研究表明，SSP 中 N 端跨膜区的 S27 和 GP2 跨膜区的 V431、F434 和 V435 影响伊曲康唑的抗 LASV 活性。伊曲康唑对引起出血热的五种新世界（NW）哺乳动物沙粒病毒也具有抗病毒活性。这项研究促进了伊曲康唑在治疗人类致病性沙粒病毒方面的潜在再利用，并为基于独特的 SSP-GP2 界面预测结构特征的沙粒病毒融合抑制剂的进一步结构优化提供了基础。
