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The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo

(2018) ANTIVIRAL RESEARCH. 157. p.151-158
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Abstract
Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and a member of the genus Orthohepevirus in the family Hepeviridae. HEV infections are the common cause of acute hepatitis but can also take chronic courses. Ribavirin is the treatment of choice for most patients and type I interferon (IFN) has been evaluated in a few infected transplantation patients in vivo. However, no effective and specific treatments against HEV infections are currently available. In this study, we evaluated the natural compound silvestrol, isolated from the plant Aglaia foveolata, and known for its specific inhibition of the DEAD-box RNA helicase eIF4A in state-of-the-art HEV experimental model systems. Silvestrol blocked HEV replication of different subgenomic replicons in a dose-dependent manner at low nanomolar concentrations and acted additive to ribavirin (RBV). In addition, HEV p6-based full length replication and production of infectious particles was reduced in the presence of silvestrol. A pangenotypic effect of the compound was further demonstrated with primary isolates from four different human genotypes in HEV infection experiments of hepatocyte-like cells derived from human embryonic and induced pluripotent stem cells. In vivo, HEV RNA levels rapidly declined in the feces of treated mice while no effect was observed in the vehicle treated control animals. In conclusion, silvestrol could be identified as pangenotypic HEV replication inhibitor in vitro with additive effect to RBV and further demonstrated high potency in vivo. The compound therefore may be considered in future treatment strategies of chronic hepatitis E in immunocompromised patients.
Keywords
Hepatitis E virus (HEV), Silvestrol, Antiviral activity, Host target, Replication, Humanized mice, RIBAVIRIN TREATMENT FAILURE, TRANSLATION INITIATION, HUMAN LIVER, INFECTION, CELLS, RIBOSOMES, LYMPHOMA, GENOME, CANCER, MODEL

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Citation

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MLA
Todt, Daniel et al. “The Natural Compound Silvestrol Inhibits Hepatitis E Virus (HEV) Replication in Vitro and in Vivo.” ANTIVIRAL RESEARCH 157 (2018): 151–158. Print.
APA
Todt, D., Moeller, N., Praditya, D., Kinast, V., Friesland, M., Engelmann, M., Verhoye, L., et al. (2018). The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo. ANTIVIRAL RESEARCH, 157, 151–158.
Chicago author-date
Todt, Daniel, Nora Moeller, Dimas Praditya, Volker Kinast, Martina Friesland, Michael Engelmann, Lieven Verhoye, et al. 2018. “The Natural Compound Silvestrol Inhibits Hepatitis E Virus (HEV) Replication in Vitro and in Vivo.” Antiviral Research 157: 151–158.
Chicago author-date (all authors)
Todt, Daniel, Nora Moeller, Dimas Praditya, Volker Kinast, Martina Friesland, Michael Engelmann, Lieven Verhoye, Ibrahim Ibrahim Mahmoud Sayed, Patrick Behrendt, Viet Loan Dao Thi, Philip Meuleman, and Eike Steinmann. 2018. “The Natural Compound Silvestrol Inhibits Hepatitis E Virus (HEV) Replication in Vitro and in Vivo.” Antiviral Research 157: 151–158.
Vancouver
1.
Todt D, Moeller N, Praditya D, Kinast V, Friesland M, Engelmann M, et al. The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo. ANTIVIRAL RESEARCH. 2018;157:151–8.
IEEE
[1]
D. Todt et al., “The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo,” ANTIVIRAL RESEARCH, vol. 157, pp. 151–158, 2018.
@article{8576094,
  abstract     = {Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and a member of the genus Orthohepevirus in the family Hepeviridae. HEV infections are the common cause of acute hepatitis but can also take chronic courses. Ribavirin is the treatment of choice for most patients and type I interferon (IFN) has been evaluated in a few infected transplantation patients in vivo. However, no effective and specific treatments against HEV infections are currently available. 
In this study, we evaluated the natural compound silvestrol, isolated from the plant Aglaia foveolata, and known for its specific inhibition of the DEAD-box RNA helicase eIF4A in state-of-the-art HEV experimental model systems. Silvestrol blocked HEV replication of different subgenomic replicons in a dose-dependent manner at low nanomolar concentrations and acted additive to ribavirin (RBV). In addition, HEV p6-based full length replication and production of infectious particles was reduced in the presence of silvestrol. A pangenotypic effect of the compound was further demonstrated with primary isolates from four different human genotypes in HEV infection experiments of hepatocyte-like cells derived from human embryonic and induced pluripotent stem cells. In vivo, HEV RNA levels rapidly declined in the feces of treated mice while no effect was observed in the vehicle treated control animals. In conclusion, silvestrol could be identified as pangenotypic HEV replication inhibitor in vitro with additive effect to RBV and further demonstrated high potency in vivo. The compound therefore may be considered in future treatment strategies of chronic hepatitis E in immunocompromised patients.},
  author       = {Todt, Daniel and Moeller, Nora and Praditya, Dimas and Kinast, Volker and Friesland, Martina and Engelmann, Michael and Verhoye, Lieven and Ibrahim Mahmoud Sayed, Ibrahim and Behrendt, Patrick and Dao Thi, Viet Loan and Meuleman, Philip and Steinmann, Eike},
  issn         = {0166-3542},
  journal      = {ANTIVIRAL RESEARCH},
  keywords     = {Hepatitis E virus (HEV),Silvestrol,Antiviral activity,Host target,Replication,Humanized mice,RIBAVIRIN TREATMENT FAILURE,TRANSLATION INITIATION,HUMAN LIVER,INFECTION,CELLS,RIBOSOMES,LYMPHOMA,GENOME,CANCER,MODEL},
  language     = {eng},
  pages        = {151--158},
  title        = {The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo},
  url          = {http://dx.doi.org/10.1016/j.antiviral.2018.07.010},
  volume       = {157},
  year         = {2018},
}

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