1. Academic Validation
  2. Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona- and picornaviruses

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

  • Antiviral Res. 2018 Feb;150:123-129. doi: 10.1016/j.antiviral.2017.12.010.
Christin Müller 1 Falk W Schulte 2 Kerstin Lange-Grünweller 2 Wiebke Obermann 2 Ramakanth Madhugiri 3 Stephan Pleschka 1 John Ziebuhr 1 Roland K Hartmann 2 Arnold Grünweller 4
Affiliations

Affiliations

  • 1 Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392 Gießen, Germany; Deutsches Zentrum für Infektionsforschung (DZIF) at the partner site Gießen-Marburg-Langen, Germany.
  • 2 Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, Germany.
  • 3 Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392 Gießen, Germany.
  • 4 Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, Germany. Electronic address: [email protected].
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. EC50 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 EC50 value of 20 nM silvestrol was determined in MRC-5 cells. The higher EC50 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.

Keywords

Cap-dependent translation; Coronavirus; IRES; Picornavirus; Silvestrol; eIF4A.

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