Screening and Identification of Lujo Virus Entry Inhibitors From an Food and Drug Administration-Approved Drugs Library

Frontiers in Microbiology

Ming Tian¹  Minmin Zhou²  Yuxia Hou²  Junyuan Cao²  Xiaoying Jia²  Wei Wang²  Jiao Guo²  Siqi Dong²  Gengfu Xiao²  Yueli Zhang³  Yang Liu⁴ 

[1] College of Chemistry, Central China Normal University, Wuhan, China;College of Life Science, University of Chinese Academy of Sciences, Beijing, China;College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China;State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China;

关键词: Lujo virus;    glycoprotein complex;    entry inhibitor;    mammarenavirus;    trametinib;    manidipine;   

DOI  :  10.3389/fmicb.2021.793519

来源: DOAJ

【 摘 要 】

Lujo virus (LUJV) belongs to the Old World (OW) genus Mammarenavirus (family Arenaviridae). It is categorized as a biosafety level (BSL) 4 agent. Currently, there are no U.S. Food and Drug Administration (FDA)-approved drugs or vaccines specifically for LUJV or other pathogenic OW mammarenaviruses. Here, a high-throughput screening of an FDA-approved drug library was conducted using pseudotype viruses bearing LUJV envelope glycoprotein (GPC) to identify inhibitors of LUJV entry. Three hit compounds, trametinib, manidipine, and lercanidipine, were identified as LUJV entry inhibitors in the micromolar range. Mechanistic studies revealed that trametinib inhibited LUJV GPC-mediated membrane fusion by targeting C410 [located in the transmembrane (TM) domain], while manidipine and lercanidipine inhibited LUJV entry by acting as calcium channel blockers. Meanwhile, all three hits extended their antiviral spectra to the entry of other pathogenic mammarenaviruses. Furthermore, all three could inhibit the authentic prototype mammarenavirus, lymphocytic choriomeningitis virus (LCMV), and could prevent infection at the micromolar level. This study shows that trametinib, manidipine, and lercanidipine are candidates for LUJV therapy and highlights the critical role of calcium in LUJV infection. The presented findings reinforce the notion that the key residue(s) located in the TM domain of GPC provide an entry-targeted platform for designing mammarenavirus inhibitors.

【 授权许可】

Unknown