Screening and Identification of Lujo Virus Entry Inhibitors From an Food and Drug Administration-Approved Drugs Library
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....
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Frontiers Media S.A.
2021
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oai:doaj.org-article:ae583dac674e48999f8255124687218c2021-12-02T11:53:33ZScreening and Identification of Lujo Virus Entry Inhibitors From an Food and Drug Administration-Approved Drugs Library1664-302X10.3389/fmicb.2021.793519https://doaj.org/article/ae583dac674e48999f8255124687218c2021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fmicb.2021.793519/fullhttps://doaj.org/toc/1664-302XLujo 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.Junyuan CaoJunyuan CaoSiqi DongSiqi DongYang LiuMinmin ZhouMinmin ZhouJiao GuoJiao GuoXiaoying JiaXiaoying JiaYueli ZhangYueli ZhangYuxia HouYuxia HouMing TianGengfu XiaoGengfu XiaoWei WangWei WangFrontiers Media S.A.articleLujo virusglycoprotein complexentry inhibitormammarenavirustrametinibmanidipineMicrobiologyQR1-502ENFrontiers in Microbiology, Vol 12 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Lujo virus glycoprotein complex entry inhibitor mammarenavirus trametinib manidipine Microbiology QR1-502 |
| spellingShingle |
Lujo virus glycoprotein complex entry inhibitor mammarenavirus trametinib manidipine Microbiology QR1-502 Junyuan Cao Junyuan Cao Siqi Dong Siqi Dong Yang Liu Minmin Zhou Minmin Zhou Jiao Guo Jiao Guo Xiaoying Jia Xiaoying Jia Yueli Zhang Yueli Zhang Yuxia Hou Yuxia Hou Ming Tian Gengfu Xiao Gengfu Xiao Wei Wang Wei Wang Screening and Identification of Lujo Virus Entry Inhibitors From an Food and Drug Administration-Approved Drugs Library |
| description |
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. |
| format |
article |
| author |
Junyuan Cao Junyuan Cao Siqi Dong Siqi Dong Yang Liu Minmin Zhou Minmin Zhou Jiao Guo Jiao Guo Xiaoying Jia Xiaoying Jia Yueli Zhang Yueli Zhang Yuxia Hou Yuxia Hou Ming Tian Gengfu Xiao Gengfu Xiao Wei Wang Wei Wang |
| author_facet |
Junyuan Cao Junyuan Cao Siqi Dong Siqi Dong Yang Liu Minmin Zhou Minmin Zhou Jiao Guo Jiao Guo Xiaoying Jia Xiaoying Jia Yueli Zhang Yueli Zhang Yuxia Hou Yuxia Hou Ming Tian Gengfu Xiao Gengfu Xiao Wei Wang Wei Wang |
| author_sort |
Junyuan Cao |
| title |
Screening and Identification of Lujo Virus Entry Inhibitors From an Food and Drug Administration-Approved Drugs Library |
| title_short |
Screening and Identification of Lujo Virus Entry Inhibitors From an Food and Drug Administration-Approved Drugs Library |
| title_full |
Screening and Identification of Lujo Virus Entry Inhibitors From an Food and Drug Administration-Approved Drugs Library |
| title_fullStr |
Screening and Identification of Lujo Virus Entry Inhibitors From an Food and Drug Administration-Approved Drugs Library |
| title_full_unstemmed |
Screening and Identification of Lujo Virus Entry Inhibitors From an Food and Drug Administration-Approved Drugs Library |
| title_sort |
screening and identification of lujo virus entry inhibitors from an food and drug administration-approved drugs library |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/ae583dac674e48999f8255124687218c |
| work_keys_str_mv |
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