The natural compound silvestrol is a potent inhibitor of Ebola virus replication

Biedenkopf, Nadine; Lange-Grünweller, Kerstin; Schulte, Falk W.; Weißer, Aileen; Müller, Christin; Becker, Dirk; Becker, Stephan; Hartmann, Roland K.; Grünweller, Arnold

doi:10.1016/j.antiviral.2016.11.011

Cited by 83 publications

(95 citation statements)

References 22 publications

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“…Long and structured 5′ UTRs are also often found in capped viral mRNAs like those from EBOV (Weik et al, 2002;Schlereth et al, 2016). In line with this, we have found that low nanomolar concentrations of silvestrol strongly reduce EBOV titers in primary human macrophages by efficiently decreasing viral protein expression without having cytotoxic side effects at concentrations of effective antiviral activity (Biedenkopf et al, 2017). Also many plus-strand (+) RNA viruses, such as corona-and picornaviruses, carry long and highly structured 5′ UTRs with important functions in viral replication and/or translation initiation (reviewed in Madhugiri et al, 2016).…”

Section: Introductionsupporting

confidence: 81%

“…We have recently identified the natural compound silvestrol as a potent antiviral molecule to inhibit Ebola virus (EBOV) replication (Biedenkopf et al, 2017). Silvestrol can be isolated from plants of the genus Aglaia.…”

Section: Introductionmentioning

confidence: 99%

“…Silvestrol is cytotoxic at low nanomolar concentrations to a large number of cancer cell lines and was also shown to exert strong antitumorigenic effects in several tumor mouse models (Cencic et al, 2009;Kogure et al, 2013;Patton et al, 2015). Importantly, in non-cancer cells and primary cells, silvestrol seems to be well tolerated up to low micromolar concentrations (Su et al, 2006;Zhu et al, 2007;Biedenkopf et al, 2017). The reasons are so far not well understood, however several proto-oncogenes that are sensitive to silvestrol harbor extended 5′UTRs with extensive RNA secondary structure elements.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Introductionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…95 It has been proposed that silvestrol increases the affinity of eIF4A to mRNA, thereby stalling the helicase on its RNA substrate, which leads to a depletion of eIF4A from mRNA-bound eIF4F complexes. 97 More recently, silvestrol has been also shown to inhibit positive sense RNA genome viruses of the genera Coronavirus, Picornavirus, and Flavivirus, suggesting its potential role as broad range viral replication inhibitor. 97 More recently, silvestrol has been also shown to inhibit positive sense RNA genome viruses of the genera Coronavirus, Picornavirus, and Flavivirus, suggesting its potential role as broad range viral replication inhibitor.…”

Section: Targeting Host Factors Involved In Transcription and Replicamentioning

confidence: 99%

Antiviral Agents Against Ebola Virus Infection: Repositioning Old Drugs and Finding Novel Small Molecules

Fanunza

Frau

Corona

et al. 2018

Annual Reports in Medicinal Chemistry

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“…foveolata that suggest to use as a potential drug against Ebola Virus (EBOV) as EBOV mRNAs have 5'capping and structured 5' UTRs (Biedenkopf et al, 2017). Such recent research endeavors also highlighted the pharmacological properties of the DEAD box RNA helicases.…”

Section: Figmentioning

confidence: 99%

The DEAD-box RNA helicases and multiple abiotic stresses in plants: a systematic review of recent advances and challenges

Baruah¹,

Debbarma²,

Boruah³

et al. 2017

Plant Omics

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Major crop production does not yet match the population growth rate because multiple abiotic stresses hamper the growth and yield of these crops. Most of the plants can tolerate adverse climatic conditions by performing some adaptive machineries but to certain extent. Till date various biotechnological and molecular breeding research approaches have been directed towards developing resistance to single stress factor. However, development of crop plants resistant to a single stress is not an ideal solution in the current agriculture scenario. Occurrence of multiple stresses at a single point of time makes it difficult to formulate research strategies. Considering the huge loss of crop productivity due to these environmental factors, there is an urgent need to direct our research focus towards developing sustainable multi-stress resistance in plants to counter the adverse effect of climate change on the productivity of crops. RNA helicases are ubiquitous proteins that are found in both prokaryotes and eukaryotes. The largest RNA helicase family comprises the DEAD-box RNA helicases which are involved in many aspects of RNA metabolism and in diverse biological processes in plants including regulation of multiple abiotic stress responses. The DEAD-box RNA helicases can be considered as means to identify pathways involved in multiple abiotic stress tolerance. In this review, we summarize the recent advances in elucidating the functions of the DEAD-box RNA helicases in multiple abiotic stress responses and future challenges. We also briefly discussed about our recent research efforts (published and on-going) in this direction. This review would help to formulate new research endeavours utilizing the DEAD-box helicase genes in development of multiple abiotic stress tolerant plants through genetic engineering and biotechnology. Target specific multiplex and multigene CRISPR/Ca9 genome editing would be ideal approach to edit different abiotic stress responsive DEAD-box RNA helicase genes to develop sustainable multiple abiotic stress tolerance in crop plants.

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The natural compound silvestrol is a potent inhibitor of Ebola virus replication

Cited by 83 publications

References 22 publications

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 Agents Against Ebola Virus Infection: Repositioning Old Drugs and Finding Novel Small Molecules

The DEAD-box RNA helicases and multiple abiotic stresses in plants: a systematic review of recent advances and challenges

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