The Antiviral Effect of Novel Steroidal Derivatives on Flaviviruses

Luping Zhang,Jing Ye,Shengbo Cao,Hongyu Duan,Dengyuan Zhou,Qiuyan Li,Shaoyong Ke,Muhammad Imran,Shuo Zhu

doi:10.3389/fmicb.2021.727236

Abstract

Flaviviruses are the major emerging arthropod-borne pathogens globally. However, there is still no practical anti-flavivirus approach. Therefore, existing and emerging flaviviruses desperately need active broad-spectrum drugs. In the present study, the antiviral effect of steroidal dehydroepiandrosterone (DHEA) and 23 synthetic derivatives against flaviviruses such as Japanese encephalitis virus (JEV), Zika virus (ZIKV), and Dengue virus (DENV) were appraised by examining the characteristics of virus infection both in vitro and in vivo. Our results revealed that AV1003, AV1004 and AV1017 were the most potent inhibitors of flavivirus propagation in cells. They mainly suppress the viral infection in the post-invasion stage in a dose-dependent manner. Furthermore, orally administered compound AV1004 protected mice from lethal JEV infection by increasing the survival rate and reducing the viral load in the brain of infected mice. These results indicate that the compound AV1004 might be a potential therapeutic drug against JEV infection. These DHEA derivatives may provide lead scaffolds for further design and synthesis of potential anti-flavivirus potential drugs.

Highlights

Flaviviruses belonging to the family Flaviviridae are a group of more than 70 enveloped RNA viruses
The antiviral abilities of DHEA and its derivatives against Japanese encephalitis virus (JEV) were examined by inhibition of virus-induced cytopathogenicity effects (CPEs) in BHK-21
Dehydroepiandrosterone (DHEA) is an intermediate in testosterone biosynthesis and a typical steroid and sex hormone precursor, which can affect the formation of fat, regulate NADPH, FIGURE 8 | AV1004-treated group (AV1004) protects mice from JEV infection. (A) Monitoring the survival rate of mice in each group for 23 days after inoculation with JEV. n = 10 mice per group. (B) The clinical symptoms of the disease in mice are demonstrated on indicated days post-infection. n = 10 mice per group

Summary

Introduction

Flaviviruses belonging to the family Flaviviridae are a group of more than 70 enveloped RNA viruses. They cause severe diseases in humans and animals. Most of them are arthropod-borne viruses (arboviruses) transmitted to humans or other vertebrate hosts by insect vectors (Gubler, 2007; Fernandez-Garcia et al, 2009). The Flavivirus genus including Japanese encephalitis virus (JEV), Zika virus (ZIKV), Dengue virus (DENV), West Nile virus (WNV), tick-borne encephalitis virus (TBEV) and yellow fever virus (YFV) (Mukhopadhyay et al, 2005). Some flaviviruses can cause encephalitis and other neurological manifestations, including WNV and JEV, while some tend to cause vascular leakage and hemorrhagic disease, including DENV and YFV (King et al, 2012; Barrows et al, 2018). ZIKV has been proved to be related to the development of Guillain–Barré syndrome in adults and severe fetal microcephaly (Culshaw et al, 2018)

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Conclusion