Generation of A Stable GFP-reporter Zika Virus System for High-throughput Screening of Zika Virus Inhibitors
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RESEARCH ARTICLE
Generation of A Stable GFP-reporter Zika Virus System for High-throughput Screening of Zika Virus Inhibitors Jing-Wei Zhang1 • Han Wang1 • Jing Liu1 • Le Ma1 • Rong-Hong Hua1
•
Zhi-Gao Bu1,2
Received: 31 July 2020 / Accepted: 18 September 2020 Ó Wuhan Institute of Virology, CAS 2020
Abstract Zika virus (ZIKV) is associated with severe birth defects and Guillain-Barre´ syndrome and no approved vaccines or specific therapies to combat ZIKV infection are currently available. To accelerate anti-ZIKV therapeutics research, we developed a stable ZIKV GFP-reporter virus system with considerably improved GFP visibility and stability. In this system a BHK-21 cell line expressing DC-SIGNR was established to facilitate the proliferation of GFP-reporter ZIKV. Using this reporter virus system, we established a high-throughput screening assay and screened a selected plant-sourced compounds library for their ability to block ZIKV infection. More than 31 out of 974 tested compounds effectively decreased ZIKV reporter infection. Four selected compounds, homoharringtonine (HHT), bruceine D (BD), dihydroartemisinin (DHA) and digitonin (DGT), were further validated to inhibit wild-type ZIKV infection in cells of BHK-21 and human cell line A549. The FDA-approved chronic myeloid leukemia treatment drug HHT and BD were identified as broad-spectrum flavivirus inhibitors. DHA, another FDA-approved antimalarial drug effectively inhibited ZIKV infection in BHK-21 cells. HHT, BD and DHA inhibited ZIKV infection at a post-entry stage. Digitonin was found to have inhibitory activity in the early stage of viral infection. Our research provides an efficient high-throughput screening assay for ZIKV inhibitors. The active compounds identified in this study represent potential therapies for the treatment of ZIKV infection. Keywords Zika virus (ZIKV) GFP reporter virus High-throughput screening Antiviral drug discovery
Introduction Although Zika virus (ZIKV) was discovered 70 years ago (Dick et al. 1952), the virus has not caused a large-scale outbreak or serious infections and has therefore received
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12250-020-00316-0) contains supplementary material, which is available to authorized users.
& Zhi-Gao Bu [email protected] & Rong-Hong Hua [email protected] 1
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China
2
Jiangsu Co-Innovation Centre for Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou University, Yangzhou 225009, China
little attention. The massive ZIKV outbreak in Brazil in 2015 linked ZIKV infections with severe neurological complications such as Guillain-Barre´ syndrome (GBS) in adults and congenital malformations in the fetuses of women infected with ZIKV during pregnancy (Petersen et al. 2016; F
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