Flavivirus pathogens are taxonomically classified in the genus Flavivirus and family Flaviviridae. These viruses comprise over 70 different pathogens such as Japanese encephalitis virus (JEV), Zika virus (ZIKV), dengue virus (DENV), West Nile virus (WNV), and yellow fever virus (YFV). Most flaviviruses are arthropod-borne and cause public health problems worldwidely. However, flavivirus-induced diseases are still pandemic and few therapies beyond intensive supportive care are currently available.

In the present study, the research group led by Prof. XIAO Gengfu from Wuhan Institute of Virology of the Chinese Academy of Sciences screened an FDA-drugs library with 1018 compounds and identified five hit drugs, especially calcium inhibitors, exerting ant 41 i-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.

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+ 30 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 infectionThe study provided novel insights into the molecular mechanisms underlying flavivirus infection, and offer new and promising therapeutic possibilities for combating infections caused by flavivirus.

The results have been published in Journal of Virology entitled "Screening of FDA-1 Approved Drugs for Inhibitors against Japanese Encephalitis Virus Infection".

This work was supported by the National Natural Sciences Foundation of China.

Selection and characterization of manidipine-resistant JEV

Contact

WANG Wei

Email: wangwei@wh.iov.cn

Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China (http://english.whiov.cas.cn/)