Antiviral Activity of Compound L3 against Dengue and Zika Viruses In Vitro and In Vivo.

Fu-Kai Chuang,Ching-Len Liao,Pei-Ling Tsai,Chih-Chin Shih,Yu-Lung Chiu,Tsung-Hsien Chang,Chang-Chi Lin,Bo-Cyuan Su,Ming-Kuan Hu,Shih-Ming Huang,An-Rong Lee,Li-Chen Yen,Yi-Lin Chiu

doi:10.3390/ijms21114050

Abstract

Dengue virus (DENV) and Zika virus (ZIKV) are mosquito-borne flaviviruses that cause severe illness after infection. Currently, there are no specific or effective treatments against DENV and ZIKV. Previous studies have shown that tyrosine kinase activities and signal transduction are involved in flavivirus replication, suggesting a potential therapeutic strategy for DENV and ZIKV. In this study, we found that compound L3 can significantly reduce viral protein expression and viral titers in HEK-293, MCF-7, HepG2, and Huh-7 cells and exhibits superior therapeutic efficacy against flaviviral infection compared to other tyrosine kinase inhibitors. In addition, compound L3 can decrease endogenous HER2 activation and inhibit the phosphorylation of the HER2 downstream signaling molecules Src and ERK1/2, the levels of which have been associated with viral protein expression in MCF-7 cells. Moreover, silencing HER2 diminished DENV-2 and ZIKV expression in MCF-7 cells, which suggests that HER2 activity is involved in flavivirus replication. Furthermore, in DENV-2-infected AG129 mice, treatment with compound L3 increased the survival rates and reduced the viremia levels. Overall, compound L3 demonstrates therapeutic efficacy both in vitro and in vivo and could be developed as a promising antiviral drug against emerging flaviviruses or for concurrent DENV and ZIKV outbreaks.

Highlights

Flaviviruses comprise several medically important viruses, including Japanese encephalitis virus, West Nile virus, dengue virus (DENV), yellow fever virus, and Zika virus (ZIKV)
Treatment with compound L3 effectively inhibited DENV-2 viral protein expression compared to afatinib (Figure 1C) and compounds 10b and L1 (Figure 1D) in HEK-293 cells during DENV-2 infection
As several studies have shown that DENV and ZIKV concurrently outbreak in endemic areas [28,29], the development of antiviral agents that act on the host factors are more likely to have pan-antiviral activity, acting against DENV and simultaneously against related flaviviruses, such as ZIKV

Summary

Introduction

Flaviviruses comprise several medically important viruses, including Japanese encephalitis virus, West Nile virus, dengue virus (DENV), yellow fever virus, and Zika virus (ZIKV). Large outbreaks of DENV and ZIKV have occurred recently, leading to many cases of infection and illness ranging from dengue fever (DF) to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) [2,3]. ZIKV infection causes congenital malformations in the fetus, such as microcephaly, and neurological abnormalities in infected adults [4,5]. Despite decades of effort, there are still no specific antiviral drugs approved for the treatment of DENV and ZIKV infection. The development of anti-flaviviral drugs is crucially needed to decrease the severity and fatality of these diseases

Methods

Results

Conclusion