Identification of Novel Natural Products as Effective and Broad-Spectrum Anti-Zika Virus Inhibitors.

Gao Gao,Chen Chen,Du Du,Wang Wang,Li Li,Debnath Debnath,Tai Tai,Jiang Jiang

doi:10.3390/v11111019

Gao Gao, Chen Chen + Show 6 more

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https://doi.org/10.3390/v11111019

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Abstract

Zika virus (ZIKV) infection during pregnancy leads to severe congenital Zika syndrome, which includes microcephaly and other neurological malformations. No therapeutic agents have, so far, been approved for the treatment of ZIKV infection in humans; as such, there is a need for a continuous effort to develop effective and safe antiviral drugs to treat ZIKV-caused diseases. After screening a natural product library, we have herein identified four natural products with anti-ZIKV activity in Vero E6 cells, including gossypol, curcumin, digitonin, and conessine. Except for curcumin, the other three natural products have not been reported before to have anti-ZIKV activity. Among them, gossypol exhibited the strongest inhibitory activity against almost all 10 ZIKV strains tested, including six recent epidemic human strains. The mechanistic study indicated that gossypol could neutralize ZIKV infection by targeting the envelope protein domain III (EDIII) of ZIKV. In contrast, the other natural products inhibited ZIKV infection by targeting the host cell or cell-associated entry and replication stages of ZIKV. A combination of gossypol with any of the three natural products identified in this study, as well as with bortezomib, a previously reported anti-ZIKV compound, exhibited significant combinatorial inhibitory effects against three ZIKV human strains tested. Importantly, gossypol also demonstrated marked potency against all four serotypes of dengue virus (DENV) human strains in vitro. Taken together, this study indicates the potential for further development of these natural products, particularly gossypol, as the lead compound or broad-spectrum inhibitors against ZIKV and other flaviviruses, such as DENV.

Highlights

Zika virus (ZIKV) is a mosquito-borne flavivirus in the same genus as other important human pathogens, including dengue virus (DENV), West Nile virus (WNV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV) [1]
The IC90 values of these natural products against ZIKV PAN2016 strain were calculated, equal to about 6.91, 47.69, 7.91, and 31.82 μM, respectively, for gossypol, curcumin, digitonin, and conessine (Figure S1), which were slightly higher than the respective IC50 values, but much lower than the corresponding CC50 values
The results showed that gossypol potently blocked binding of envelope protein domain III (EDIII)-specific monoclonal antibody (mAb) SMZAb5, ZKA64-LALA, ZV-67, or Z004 to EDIII protein in a dose-dependent manner, with IC50 values of 7.32, 5.72, 11.7, and 22.2 μM, respectively, whereas the DMSO control showed no blockage of this binding (Figure 4D)

Summary

Introduction

Zika virus (ZIKV) is a mosquito-borne flavivirus in the same genus as other important human pathogens, including dengue virus (DENV), West Nile virus (WNV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV) [1]. Viruses 2019, 11, 1019 and fetal death, have been approved This calls for the development of safe and effective therapeutic agents against ZIKV infection in humans. The life cycle of ZIKV involves several crucial steps, including viral attachment to target cell receptors or cofactors, receptor-mediated endocytosis (viral entry), virus–endosomal membrane fusion, and postentry or post-translation stages [9,10]. In this life cycle, E protein plays a key role in viral entry into target cells and subsequent fusion of virus and cell membranes; ZIKV

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