4 years ago

Screening of FDA-Approved Drugs for Inhibitors against Japanese Encephalitis Virus Infection.

Wang W, Guo J, Zhang L, Wang P, Xiao G, Liu Y, Wang S
Japanese encephalitis virus (JEV), an arthropod-borne flavivirus, is a major cause of acute viral encephalitis in humans. There is no approved drug available for JEV-specific treatment, and the vaccines are not effective against all clinical JEV isolates. Herein, a high-throughput screening was performed against JEV from an FDA-approved drug library. Five hit drugs were identified that inhibited JEV infection with a selective index > 10. Antiviral activities of these five hit drugs against other flavivirus, including Zika virus, were also validated. As three of the five hit drugs were calcium inhibitors, additional types of calcium inhibitors were utilized that confirmed calcium was essential for JEV infection, most likely during viral replication. Adaptive mutant analysis uncovered that replacement of Q130, located in transmembrane domain 3 of the non-structural NS4B protein while relatively conserved in flavivirus, with R or K conferred JEV resistance to manidipine, a voltage-gated Ca2+ channel (VGCC) inhibitor, without apparent loss of the viral growth profile. Furthermore, manidipine was indicated to protect mice against JEV-induced lethality by decreasing viral load in brain, while abrogating histopathological changes associated with JEV infection. This study provided five anti-flavivirus candidates and identified cytoplasmic calcium as a novel antiviral target for treatment of JEV infection. The findings reported here provide therapeutic possibilities for combating infections caused by flavivirus.IMPORTANCE Currently there is no approved therapy to treat Japanese Encephalitis Virus infection. Repurposing of the approved drugs will accelerate the development of the therapeutic stratagem. In this study, we screened an FDA-drugs library and identified five hit drugs, especially calcium inhibitors, exerting anti-flavivirus activity that blocked viral replication. The in vivo efficacy and toxicity of manidipine were investigated with a JEV-infected mouse model and the viral target was identified by generating adaptive mutant.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28814523

DOI: PubMed:28814523

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