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

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.

Comparison of broad-spectrum antiviral activities of the synthetic rocaglate CR-31-B (−) and the eIF4A-inhibitor Silvestrol

“…Silvestrol inhibits the replication of RNA viruses representing different virus families, such as Ebola-(EBOV), corona-(CoV), Zika-(ZIKV), Chikungunya-(CHIKV) and hepatitis E (HEV) viruses (Müller et al, 2018a;Biedenkopf et al, 2017;Elgner et al, 2018;Glitscher et al, 2018;Henss et al, 2018). Notably, Silvestrol showed good bioavailability (Sarahdi et al, 2011), in vivo antiviral activity (Todt et al, 2018) and remarkably low https://doi.org/10. 1016/j.antiviral.2020.104706 Received 26 September 2019; Received in revised form 4 January 2020; Accepted 8 January 2020 cytotoxicity in primary cells, thus opening a broad therapeutic window for future applications.…”

Antiviral Candidates for Treating Hepatitis E Virus Infection

“…HEV is a largely understudied virus, and antiviral development has been hampered by poor viral replication levels in cell culture systems (32) and difficulties in purifying the viral polymerase in its active form (25,33). As such, several HEV replicons have been constructed from various infectious clones (34)(35)(36)(37)(38), which have allowed for effective preclinical screening of antiviral candidates (39)(40)(41).…”

Eukaryotic initiation factor 4A (eIF4A) during viral infections

“…These compounds are emerging as a new antiviral therapeutic strategy whose mechanism of action is the inhibition of eIF4A. Consistent with this, silvestrol has shown antiviral activity in vitro against RNA viruses: Ebola virus, hepatitis E, coronavirus, rhinovirus, and poliovirus [59,[63][64][65]. Hippuristanol has been tested in preclinical studies for possible use in patients with HTLV-1 [31].…”