Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona- and picornaviruses

Abstract

Coronaviruses (CoV) and picornaviruses are plus-strand RNA viruses that use 5' cap-dependent and cap-independent strategies, respectively, for viral mRNA translation initiation. Here, we analyzed the effects of the plant compound silvestrol, a specific inhibitor of the DEAD-box RNA helicase eIF4A, on viral translation using a dual luciferase assay and virus-infected primary cells. Silvestrol was recently shown to have potent antiviral activity in Ebola virus-infected human macrophages. We found that silvestrol is also a potent inhibitor of cap-dependent viral mRNA translation in CoV-infected human embryonic lung fibroblast (MRC-5) cells. EC values of 1.3 nM and 3 nM silvestrol were determined for MERS-CoV and HCoV-229E, respectively. For the highly pathogenic MERS-CoV, the potent antiviral activities of silvestrol were also confirmed using peripheral blood mononuclear cells (PBMCs) as a second type of human primary cells. Silvestrol strongly inhibits the expression of CoV structural and nonstructural proteins (N, nsp8) and the formation of viral replication/transcription complexes. Furthermore, potential antiviral effects against human rhinovirus (HRV) A1 and poliovirus type 1 (PV), representing different species in the genus Enterovirus (family Picornaviridae), were investigated. The two viruses employ an internal ribosomal entry site (IRES)-mediated translation initiation mechanism. For PV, which is known to require the activity of eIF4A, an EC value of 20 nM silvestrol was determined in MRC-5 cells. The higher EC value of 100 nM measured for HRV A1 indicates a less critical role of eIF4A activity in HRV A1 IRES-mediated translation initiation. Taken together, the data reveal a broad-spectrum antiviral activity of silvestrol in infected primary cells by inhibiting eIF4A-dependent viral mRNA translation.

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

“…Viral mRNAs also contain structured 5′-UTRs (Madhugiri et al, 2015;Schlereth et al, 2016), suggesting that viral protein synthesis may also be eIF4A-dependent. Indeed, we have shown that the specific eIF4A inhibitor Silvestrol, a plant-derived rocaglate, has broad-spectrum antiviral activity at non-cytotoxic concentrations in a low nanomolar range (Müller et al, 2018a). 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).…”

“…Indeed, we have shown that the specific eIF4A inhibitor Silvestrol, a plant-derived rocaglate, has broad-spectrum antiviral activity at non-cytotoxic concentrations in a low nanomolar range (Müller et al, 2018a). 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.…”

Focus on Middle East respiratory syndrome coronavirus (MERS-CoV)

“…This blocks helicase activity and inhibits protein translation. A recent in vitro study demonstrated that silvestrol has anti-MERS-CoV activity [73]. No clinical data or studies support its use in vivo at the present time.…”

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

“…Inhibition of viral propagation by treatment with silvestrol occurred more rapidly than any effects on cellular functions and an IC 50 lower than 1 nM was observed (Biedenkopf et al, 2017). Very recently, potent antiviral activities were also reported for coronaviruses including MERS-CoV and picornaviruses revealing broad-spectrum activities (Muller et al, 2018). For HEV, we observed also an antiviral activity at low nanomolar concentrations for the human gts 1 and 3, a gt3 swine isolate as well as for a viral variant, which was identified in HEV-infected patients and confers enhanced replication fitness (Fig.…”