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

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 inte...

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Autores principales: Todt, Daniel, Moeller, Nora, Praditya, Dimas, Kinast, Volker, Friesland, Martina, Engelmann, Michael, Verhoye, Lieven, Sayed, Ibrahim M., Behrendt, Patrick, Dao Thi, Viet Loan, Meuleman, Philip, Steinmann, Eike
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Authors. Published by Elsevier B.V. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113770/
https://www.ncbi.nlm.nih.gov/pubmed/30036559
http://dx.doi.org/10.1016/j.antiviral.2018.07.010
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author Todt, Daniel
Moeller, Nora
Praditya, Dimas
Kinast, Volker
Friesland, Martina
Engelmann, Michael
Verhoye, Lieven
Sayed, Ibrahim M.
Behrendt, Patrick
Dao Thi, Viet Loan
Meuleman, Philip
Steinmann, Eike
author_facet Todt, Daniel
Moeller, Nora
Praditya, Dimas
Kinast, Volker
Friesland, Martina
Engelmann, Michael
Verhoye, Lieven
Sayed, Ibrahim M.
Behrendt, Patrick
Dao Thi, Viet Loan
Meuleman, Philip
Steinmann, Eike
author_sort Todt, Daniel
collection PubMed
description 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.
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spelling pubmed-71137702020-04-02 The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo Todt, Daniel Moeller, Nora Praditya, Dimas Kinast, Volker Friesland, Martina Engelmann, Michael Verhoye, Lieven Sayed, Ibrahim M. Behrendt, Patrick Dao Thi, Viet Loan Meuleman, Philip Steinmann, Eike Antiviral Res Article 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. The Authors. Published by Elsevier B.V. 2018-09 2018-07-20 /pmc/articles/PMC7113770/ /pubmed/30036559 http://dx.doi.org/10.1016/j.antiviral.2018.07.010 Text en © 2018 The Authors Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Todt, Daniel
Moeller, Nora
Praditya, Dimas
Kinast, Volker
Friesland, Martina
Engelmann, Michael
Verhoye, Lieven
Sayed, Ibrahim M.
Behrendt, Patrick
Dao Thi, Viet Loan
Meuleman, Philip
Steinmann, Eike
The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo
title The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo
title_full The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo
title_fullStr The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo
title_full_unstemmed The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo
title_short The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo
title_sort natural compound silvestrol inhibits hepatitis e virus (hev) replication in vitro and in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113770/
https://www.ncbi.nlm.nih.gov/pubmed/30036559
http://dx.doi.org/10.1016/j.antiviral.2018.07.010
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