Department of Emerging Infectious Diseases, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki 852-8523, Japan.
Program for Nurturing Global Leaders in Tropical and Emerging Communicable Diseases, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan.
Viruses. 2022 Dec 30;15(1):105. doi: 10.3390/v15010105.
Although many arenaviruses cause severe diseases with high fatality rates each year, treatment options are limited to off-label use of ribavirin, and a Food and Drug Administration (FDA)-approved vaccine is not available. To identify novel therapeutic candidates against arenaviral diseases, an RNA polymerase I-driven minigenome (MG) expression system for Lassa virus (LASV) was developed and optimized for high-throughput screening (HTS). Using this system, we screened 2595 FDA-approved compounds for inhibitors of LASV genome replication and identified multiple compounds including pixantrone maleate, a topoisomerase II inhibitor, as hits. Other tested topoisomerase II inhibitors also suppressed LASV MG activity. These topoisomerase II inhibitors also inhibited Junin virus (JUNV) MG activity and effectively limited infection by the JUNV Candid #1 strain, and siRNA knockdown of both topoisomerases (IIα and IIβ) restricted JUNV replication. These results suggest that topoisomerases II regulate arenavirus replication and can serve as molecular targets for panarenaviral replication inhibitors.
虽然许多沙粒病毒每年都会导致严重疾病和高死亡率，但治疗选择仅限于利巴韦林的标签外使用，并且没有获得食品和药物管理局 (FDA) 批准的疫苗。为了确定针对沙粒病毒病的新型治疗候选物，开发了一种 RNA 聚合酶 I 驱动的小基因组 (MG) 表达系统用于拉萨病毒 (LASV)，并针对高通量筛选 (HTS) 进行了优化。使用该系统，我们筛选了 2595 种 FDA 批准的化合物，以寻找 LASV 基因组复制的抑制剂，并鉴定出多种化合物，包括拓扑异构酶 II 抑制剂 pixantrone 马来酸盐，作为有效化合物。其他测试的拓扑异构酶 II 抑制剂也抑制了 LASV MG 活性。这些拓扑异构酶 II 抑制剂还抑制了胡宁病毒 (JUNV) MG 活性，并有效限制了 JUNV Candid #1 株的感染，以及拓扑异构酶 (IIα 和 IIβ) 的 siRNA 敲低都限制了 JUNV 的复制。这些结果表明，拓扑异构酶 II 调节沙粒病毒的复制，可以作为泛沙粒病毒复制抑制剂的分子靶标。
