In silico study on the Hepatitis E virus RNA Helicase and its inhibition by silvestrol, rocaglamide and other flavagline compounds

Abstract

Hepatitis E Virus (HEV) follows waterborne or zoonotic/foodborne transmission. Genotype 3 HEV infections are worldwide spread, especially in swine populations, representing an emerging threat for human health, both for farm workers and pork meat consumers. Unfortunately, HEV in vitro culture and analysis are still difficult, resulting in a poor understanding of its biology and hampering the implementation of counteracting strategies. Indeed, HEV encodes for only one non-structural multifunctional and multidomain protein (ORF1), which might be a good candidate for anti-HEV drugging strategies. In this context, an in silico molecular modelling approach that consisted in homology modelling to derive the 3D model target, docking study to simulate the binding event, and molecular dynamics to check complex stability over time was used. This workflow succeeded to describe ORF1 RNA Helicase domain from a molecular standpoint allowing the identification of potential inhibitory compounds among natural plant-based flavagline-related molecules such as silvestrol, rocaglamide and derivatives thereof. In the context of scouting potential anti-viral compounds and relying on the outcomes presented, further dedicated investigations on silvestrol, rocaglamide and a promising oxidized derivative have been suggested. For the sake of data reproducibility, the 3D model of HEV RNA Helicase has been made publicly available.

Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions

“…For instance, zinc salts were reported to directly inhibit the activity of viral RNA-dependent RNA polymerase (RdRp), leading to inhibition of viral replication ( Kaushik et al., 2017 ). Based on in silico screening methods, compounds that potentially inhibit the function of methyltransferase or helicase of ORF1 were also discovered ( Hooda et al., 2022 ; Pedroni et al., 2022 ). These compounds may hold potential as direct acting antivirals in controlling HEV infection.…”

Silvestrol alleviates glioblastoma progression through ERK pathway modulation and MANBA and NRG-1 expression

“…Silvestrol, a small molecule extracted from natural plants, has demonstrated clear therapeutic effects on tumors, as well as significant inhibitory effects on viruses, including the hepatitis E virus [30], Ebola virus [31], and Chikungunya Virus [32]. As a potent eukaryotic initiation factor 4A (EIF4A) inhibitor, the precise antitumor and antiviral pathways of silvestrol have yet to be fully elucidated.…”