Mizuma Keita, Hashizume Mei, Urata Shuzo, Shindo Keiko, Takashima Ayako, Mizuta Satoshi, Iwasaki Masaharu
Laboratory of Emerging Viral Diseases, International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
Present address: Division of Risk Analysis and Management, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan.
J Gen Virol. 2024 Dec;105(12). doi: 10.1099/jgv.0.002060.
Lassa virus (LASV) is an Old World (OW) mammarenavirus that causes Lassa fever, a life-threatening acute febrile disease endemic in West Africa. Lymphocytic choriomeningitis virus (LCMV) is a worldwide-distributed, prototypic OW mammarenavirus of clinical significance that has been largely neglected as a human pathogen. No licensed OW mammarenavirus vaccines are available, and the current therapeutic option is limited to the off-label use of ribavirin, which offers only partial efficacy. This situation underscores the urgent need to develop novel antivirals against human pathogenic mammarenaviruses. Previously, we showed that afatinib, a pan-ErbB tyrosine kinase inhibitor, inhibited multiple steps of the life cycles of OW LASV and LCMV, as well as the New World Junín virus vaccine strain Candid#1. In the present study, we investigated the inhibitory effect of U-73122, a phospholipase C inhibitor that acts downstream of ErbB signalling, on LCMV multiplication. U-73122 inhibited WT recombinant (r) LCMV multiplication in cultured cells. Preincubation of cell-free LCMV virions with U-73122 resulted in impaired virion infectivity. U-73122 also inhibited the infection of rLCMVs expressing heterologous viral glycoproteins, including the vesicular stomatitis Indiana virus (VSIV) glycoprotein, whereas WT VSIV infection was not affected by U-73122 treatment. Our results show the novel bioactivity of U-73122 as an LCMV inhibitor and indicate the presence of a virion-associated molecule that is necessary for virion infectivity and can be exploited as a potential antiviral drug target against human pathogenic mammarenavirus infections.
拉沙病毒（LASV）是一种旧世界（OW）沙粒病毒，可引起拉沙热，这是一种在西非流行的危及生命的急性发热性疾病。淋巴细胞性脉络丛脑膜炎病毒（LCMV）是一种在全球范围内分布的具有临床意义的原型OW沙粒病毒，在很大程度上被忽视作为一种人类病原体。目前尚无获得许可的OW沙粒病毒疫苗，当前的治疗选择仅限于利巴韦林的非标签使用，其疗效有限。这种情况凸显了开发针对人类致病性沙粒病毒的新型抗病毒药物的迫切需求。此前，我们发现阿法替尼，一种泛ErbB酪氨酸激酶抑制剂，可抑制OW LASV和LCMV以及新世界胡宁病毒疫苗株Candid#1生命周期的多个步骤。在本研究中，我们研究了磷脂酶C抑制剂U-73122（其作用于ErbB信号下游）对LCMV增殖的抑制作用。U-73122抑制培养细胞中野生型重组（r）LCMV的增殖。用U-73122对无细胞LCMV病毒粒子进行预孵育会导致病毒粒子感染性受损。U-73122还抑制表达异源病毒糖蛋白的rLCMV的感染，包括水疱性口炎印第安纳病毒（VSIV）糖蛋白，而野生型VSIV感染不受U-73122处理的影响。我们的结果显示了U-73122作为LCMV抑制剂的新型生物活性，并表明存在一种病毒粒子相关分子，该分子对于病毒粒子感染性是必需 的，并且可被开发为针对人类致病性沙粒病毒感染的潜在抗病毒药物靶点。
