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Halogenated Chrysins Inhibit Dengue and Zika Virus Infectivity.

ABSTRACT: Dengue virus infection is a global threat for which no specific treatment has not been established. Previous reports suggested chrysin and flavanone derivatives were potential flaviviral inhibitors. Here, we reported two halogenated chrysins, abbreviated FV13 and FV14, were highly potent against DENV1-4 and ZIKV infectivities with the FV13 EC50 values of 2.30?±?1.04, 1.47?±?0.86, 2.32?±?1.46, 1.78?±?0.72 and 1.65?±?0.86?µM; and FV14 EC50 values of 2.30?±?0.92, 2.19?±?0.31, 1.02?±?0.31, 1.29?±?0.60 and 1.39?±?0.11?µM, respectively. The CC50s to LLC/MK2 of FV13 and FV14 were 44.28?±?2.90??M, 42.51?±?2.53?µM, respectively. Mechanism of drug action studies suggested multiple targets but maximal efficiency was achieved with early post infection treatment. This is the first report showing a high potency of halogenated chrysins for development as a broad-spectrum anti-flaviviral drug.

SUBMITTER: Suroengrit A

PROVIDER: S-EPMC5651866 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Halogenated Chrysins Inhibit Dengue and Zika Virus Infectivity.

Suroengrit Aphinya A Yuttithamnon Wanchalerm W Srivarangkul Pimsiri P Pankaew Saran S Kingkaew Krongkan K Chavasiri Warinthorn W Boonyasuppayakorn Siwaporn S

Scientific reports 20171020 1

Dengue virus infection is a global threat for which no specific treatment has not been established. Previous reports suggested chrysin and flavanone derivatives were potential flaviviral inhibitors. Here, we reported two halogenated chrysins, abbreviated FV13 and FV14, were highly potent against DENV1-4 and ZIKV infectivities with the FV13 EC<sub>50</sub> values of 2.30 ± 1.04, 1.47 ± 0.86, 2.32 ± 1.46, 1.78 ± 0.72 and 1.65 ± 0.86 µM; and FV14 EC<sub>50</sub> values of 2.30 ± 0.92, 2.19 ± 0.31, ...[more]

PMID: 29057920

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Project description:West Nile virus (WNV) has caused multiple global outbreaks with increased frequency of neuroinvasive disease in recent years. Despite many years of research, there are no licensed therapeutics or vaccines available for human use. One of the major impediments of vaccine development against WNV is the potential enhancement of infection by related flaviviruses in vaccinated subjects through the mechanism of antibody-dependent enhancement of infection (ADE). For instance, the recent finding of enhancement of Zika virus (ZIKV) infection by pre-exposure to WNV further complicates the development of WNV vaccines. Epidemics of WNV and the potential risk of ADE by current vaccine candidates demand the development of effective and safe vaccines. We have previously reported that the domain III (DIII) of the WNV envelope protein can be readily expressed in Nicotiana benthamiana leaves, purified to homogeneity, and promote antigen-specific antibody response in mice. Herein, we further investigated the in vivo potency of a plant-made DIII (plant-DIII) in providing protective immunity against WNV infection. Furthermore, we examined if vaccination with plant-DIII would enhance the risk of a subsequent infection by ZIKV and Dengue virus (DENV). Plant-DIII vaccination evoked antigen-specific cellular immune responses as well as humoral responses. DIII-specific antibodies were neutralizing and the neutralization titers met the threshold correlated with protective immunity by vaccines against multiple flaviviruses. Furthermore, passive administration of anti-plant DIII mouse serum provided full protection against a lethal challenge of WNV infection in mice. Notably, plant DIII-induced antibodies did not enhance ZIKV and DENV infection in Fc gamma receptor-expressing cells, addressing the concern of WNV vaccines in inducing cross-reactive antibodies and sensitizing subjects to subsequent infection by heterologous flavivirus. This study provides the first report of a WNV subunit vaccine that induces protective immunity, while circumventing induction of antibodies with enhancing activity for ZIKV and DENV infection.

Project description:BackgroundEpidemiological data strongly suggest that microcephaly cases in Brazil are associated with the ongoing epidemic of Zika virus (ZIKV). In order to further solidify the possible link, we investigated the infectivity of ZIKV using various neuroblastoma (NB) cell lines.MethodsSix undifferentiated, two terminally differentiated and two retinoic acid (RA) -induced, partially differentiated cell lines were exposed to ZIKV strain PRVABC59, which is genetically similar to the French Polynesia strain, with 97-100% genetic homology to the current ZIKV strain found in Brazil. All infections were confirmed by real-time PCR (RT-qPCR), immunofluorescence assay (IFA) probing with anti-flavivirus E antibody, and evaluation of cytopathic effects.FindingsZIKV infected all six undifferentiated NB cell lines. In five out of six NB cell lines, between 90 and 70% cells were positive by IFA whereas for one cell line, CCL-127, ~80% of cells were positive for ZIKV as determined by IFA but showed persistent infection. Two differentiated cell lines, JFEN and T-268, were highly resistant to ZIKV with <1% of the cells being susceptible, as determined by IFA and confirmed by qRT-PCR. Two retinoic acid (RA)-induced NB partially differentiated cell lines showed no difference in permissiveness as compared to their undifferentiated mother cell lines.InterpretationThese findings strengthen the reported association between high incidences of microcephaly and ZIKV infection in newborns in Brazil. Our results suggest that the undifferentiated neurons are highly permissive to ZIKV infection, as one would expect during the early stages of neurogenesis in fetal brains; whereas differentiated neurons, representative of adult brain neurons, are relatively resistant to the virus, which explains the rare occurrence of neurological complications in adults infected with ZIKV. Our studies confirm the neurotropism of the ZIKV strain closely related to the current epidemic in Latin America.

Dataset Information

Halogenated Chrysins Inhibit Dengue and Zika Virus Infectivity.

Publications

Halogenated Chrysins Inhibit Dengue and Zika Virus Infectivity.

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