| Reference | [1]. J Cell Mol Med. 2020 Jun;24(12):6988-6999. doi: 10.1111/jcmm.15360. Epub 2020 May 6.<br />
Natural antiviral compound silvestrol modulates human monocyte-derived macrophages and dendritic cells.<br />
Blum L(1), Geisslinger G(1)(2), Parnham MJ(2), Grünweller A(3), Schiffmann S(2).<br />
Author information: (1)Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Frankfurt am Main, Germany. (2)Branch for Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Frankfurt am Main, Germany. (3)Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany.<br />
Outbreaks of infections with viruses like Sars-CoV-2, Ebola virus and Zika virus lead to major global health and economic problems because of limited treatment options. Therefore, new antiviral drug candidates are urgently needed. The promising new antiviral drug candidate silvestrol effectively inhibited replication of Corona-, Ebola-, Zika-, Picorna-, Hepatis E and Chikungunya viruses. Besides a direct impact on pathogens, modulation of the host immune system provides an additional facet to antiviral drug development because suitable immune modulation can boost innate defence mechanisms against the pathogens. In the present study, silvestrol down-regulated several pro- and anti-inflammatory cytokines (IL-6, IL-8, IL-10, CCL2, CCL18) and increased TNF-α during differentiation and activation of M1-macrophages, suggesting that the effects of silvestrol might cancel each other out. However, silvestrol amplified the anti-inflammatory potential of M2-macrophages by increasing expression of anti-inflammatory surface markers CD206, TREM2 and reducing release of pro-inflammatory IL-8 and CCL2. The differentiation of dendritic cells in the presence of silvestrol is characterized by down-regulation of several surface markers and cytokines indicating that differentiation is impaired by silvestrol. In conclusion, silvestrol influences the inflammatory status of immune cells depending on the cell type and activation status.<br />
DOI: 10.1111/jcmm.15360 PMCID: PMC7267175 PMID: 32374474 [Indexed for MEDLINE]<br />
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[2]. Viruses. 2018 Oct 30;10(11):592. doi: 10.3390/v10110592.<br />
Silvestrol Inhibits Chikungunya Virus Replication.<br />
Henss L(1), Scholz T(2), Grünweller A(3), Schnierle BS(4).<br />
Author information: (1)Paul-Ehrlich-Institut, Department of Virology, 63225 Langen, Germany. [email protected]. (2)Paul-Ehrlich-Institut, Department of Virology, 63225 Langen, Germany. [email protected]. (3)Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, 35032 Marburg, Germany. [email protected]. (4)Paul-Ehrlich-Institut, Department of Virology, 63225 Langen, Germany. [email protected].<br />
Silvestrol, a natural compound that is isolated from plants of the genus Aglaia, is a specific inhibitor of the RNA helicase eIF4A, which unwinds RNA secondary structures in 5'-untranslated regions (UTRs) of mRNAs and allows translation. Silvestrol has a broad antiviral activity against multiple RNA virus families. Here, we show that silvestrol inhibits the replication of chikungunya virus (CHIKV), a positive single-stranded RNA virus. Silvestrol delayed the protein synthesis of non-structural (nsPs) and structural proteins, resulting in a delayed innate response to CHIKV infection. Interferon-α induced STAT1 phosphorylation was not inhibited nor did eIF2α become phosphorylated 16 h post infection in the presence of silvestrol. In addition, the host protein shut-off induced by CHIKV infection was decreased in silvestrol-treated cells. Silvestrol acts by limiting the amount of nsPs, and thereby reducing CHIKV RNA replication. From our results, we propose that inhibition of the host helicase eIF4A might have potential as a therapeutic strategy to treat CHIKV infections.<br />
DOI: 10.3390/v10110592 PMCID: PMC6266838 PMID: 30380742 [Indexed for MEDLINE]<br />
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[3]. Clin Transl Radiat Oncol. 2020 Jul 24;24:123-126. doi: 10.1016/j.ctro.2020.07.002. eCollection 2020 Sep.<br />
The eIF4A inhibitor silvestrol sensitizes T-47D ductal breast carcinoma cells to external-beam radiotherapy.<br />
Webb TE(1), Davies M(2)(3), Maher J(3)(4)(5), Sarker D(2)(6).<br />
Author information: (1)Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK. (2)Research Oncology, Comprehensive Cancer Centre, 3rd Floor Bermondsey Wing, Guy's Hospital, Great Maze, Pond Road, London SE1 9RT, UK. (3)King's College London, School of Cancer and Pharmaceutical Sciences, Guy's Cancer Centre, Great Maze, Pond, London SE1 9RT, UK. (4)Department of Clinical Immunology and Allergy, King's College Hospital NHS Foundation Trust, Denmark, Hill, London SE5 9RS, UK. (5)Department of Immunology, Eastbourne Hospital, Kings Drive, Eastbourne, East Sussex BN21 2UD, UK. (6)Department of Medical Oncology, Guy's & St Thomas' NHS Trust, London SE1 9RT, UK.<br />
PURPOSE: eIF4A is an RNA helicase that forms part of the machinery of translation initiation.Proteomic analysis demonstrated eIF4A expression to be at least two-fold greater in a radioresistant derivative of T-47D breast cancer cells compared to parental cells.Inhibition of eIF4A has previously been shown to re-sensitize lymphomas to chemotherapeutic agents that cause DNA damage.The objective of this work is to investigate whether inhibition of eIF4A using silvestrol sensitizes breast cancer cells to radiotherapy in tissue culture, using T-47D as a model system. METHODS AND MATERIALS: T-47D cells were incubated in medium containing 0 nM to 1 nM silvestrol either for 24 h prior to irradiation at 0 Gy to 10 Gy, delivered by linear accelerator (LINAC) or continually for six days post irradiation. MTT viability and clonogenic assays were used to quantify response. RESULTS: Pre-treatment of T-47D cells with 1 nM silvestrol caused a 34% reduction (p = 0.014) in viability on irradiation at 2 Gy compared to treatment with a DMSO control, as assessed by MTT assay.Maintenance of cells in 1 nM silvestrol for six days following irradiation at 2 Gy caused a 58% reduction (p = <0.001) in tumor cell viability.Clonogenic assays performed on cells maintained in 1 nM silvestrol following irradiation showed a dose modifying factor (DMF) of 1.4 (p = <0.001, one-way ANOVA). CONCLUSIONS: Low concentrations of silvestrol sensitize T-47D breast cancer cells to radiation with minimal effects on unirradiated cells. This highlights the possible usefulness of eIF4A inhibition in potentiating radiation-induced damage at the tumor site without causing systemic toxicity.<br />
DOI: 10.1016/j.ctro.2020.07.002 PMCID: PMC7451755 PMID: 32875125<br />
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[4]. Viruses. 2018 Mar 27;10(4):149. doi: 10.3390/v10040149.<br />
Inhibition of Zika Virus Replication by Silvestrol.<br />
Elgner F(1), Sabino C(2), Basic M(3), Ploen D(4), Grünweller A(5), Hildt E(6)(7).<br />
Author information: (1)Department of Virology, Paul-Ehrlich-Institut, 63225 Langen, Germany. [email protected]. (2)Department of Virology, Paul-Ehrlich-Institut, 63225 Langen, Germany. [email protected]. (3)Department of Virology, Paul-Ehrlich-Institut, 63225 Langen, Germany. [email protected]. (4)Department of Virology, Paul-Ehrlich-Institut, 63225 Langen, Germany. [email protected]. (5)Pharmazeutische Chemie, Philipps-Universität Marburg, 35037 Marburg, Germany. [email protected]. (6)Department of Virology, Paul-Ehrlich-Institut, 63225 Langen, Germany. [email protected]. (7)German Center for Infection Research (DZIF), 38124 Braunschweig, Germany. [email protected].<br />
The Zika virus (ZIKV) outbreak in 2016 in South America with specific pathogenic outcomes highlighted the need for new antiviral substances with broad-spectrum activities to react quickly to unexpected outbreaks of emerging viral pathogens. Very recently, the natural compound silvestrol isolated from the plant Aglaia foveolata was found to have very potent antiviral effects against the (-)-strand RNA-virus Ebola virus as well as against Corona- and Picornaviruses with a (+)-strand RNA-genome. This antiviral activity is based on the impaired translation of viral RNA by the inhibition of the DEAD-box RNA helicase eukaryotic initiation factor-4A (eIF4A) which is required to unwind structured 5´-untranslated regions (5'-UTRs) of several proto-oncogenes and thereby facilitate their translation. Zika virus is a flavivirus with a positive-stranded RNA-genome harboring a 5'-capped UTR with distinct secondary structure elements. Therefore, we investigated the effects of silvestrol on ZIKV replication in A549 cells and primary human hepatocytes. Two different ZIKV strains were used. In both infected A549 cells and primary human hepatocytes, silvestrol has the potential to exert a significant inhibition of ZIKV replication for both analyzed strains, even though the ancestor strain from Uganda is less sensitive to silvestrol. Our data might contribute to identify host factors involved in the control of ZIKV infection and help to develop antiviral concepts that can be used to treat a variety of viral infections without the risk of resistances because a host protein is targeted.<br />
DOI: 10.3390/v10040149 PMCID: PMC5923443 PMID: 29584632 [Indexed for MEDLINE]<br />
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[5]. Nat Prod Rep. 2021 Jan 1;38(1):18-23. doi: 10.1039/d0np00024h. Epub 2020 Jul 23.<br />
Rocaglamide and silvestrol: a long story from anti-tumor to anti-coronavirus compounds.<br />
Schulz G(1), Victoria C, Kirschning A, Steinmann E.<br />
Author information: (1)Institute of Organic Chemistry, Leibniz University Hannover, Schneiderberg 1B, 30167 Hannover, Germany. [email protected].<br />
Covering: up to the beginning of 2020Many natural substances have been transformed again and again with regard to their pharmaceutical-medical potential, including new members of a growing class of natural products, the flavaglines. Important representatives are rocaglamide and silvestrol, isolated from the Aglaia species, which are highlighted here. These products started as potential anti-tumor agents five decades ago and have recently proved to be very promising antiviral agents, especially against RNA viruses. Today they are discussed as potential starting compounds for developing drug candidates and therapeutics.<br />
DOI: 10.1039/d0np00024h PMID: 32699874 [Indexed for MEDLINE]
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