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Project A2 - elF4A-specific RNA helicase inhibitors as potential broad-spectrum therapeutics against RNA viruses

PI
Project description

Background: The dramatic outbreak of the Ebola virus in West Africa in 2014-2015 and the occurrence of the Zika virus in Latin America in 2016 clearly demonstrate the enormous medical need to develop vaccines and antiviral drugs against emerging human pathogenic viruses. Particularly important is the development of drugs with a broad spectrum of activity because viruses can rapidly change their structures via mutations. Ideally, an antiviral drug can inhibit not only a single virus but also an entire viral family. Most previous antiviral drugs inhibit defined structures in the virus itself and are therefore highly specific. An important goal of antiviral research is the identification of human host factors that are essential for the viral life cycle (e.g., the cellular translational machinery), but whose inhibition does not result in major toxicity. An example of a suitable host factor could be the DEAD-Box RNA helicase eIF4A, which is specifically and potently blocked by the natural compound silvestrol. Silvestrol, which can be isolated from the plant Aglaia foveolata and related species, increases the affinity of eIF4A to the mRNA, which means unwinding of RNA secondary structures in 5'-untranslated regions (5'-UTRs) no longer takes place. Binding the 43S pre-initiation complex to corresponding mRNAs is then prevented, and translation is efficiently blocked. Silvestrol has been used successfully in cancer research for several years as it inhibits the translation of proto-oncogenes with structured and extended 5'UTRs. Many viral mRNAs, e.g. those of filo- or coronaviruses also have highly structured 5'UTRs. Therefore, we asked whether eIF4A might also be required for the synthesis of viral proteins.

gruenweller.text.image0 In fact, we recently demonstrated that the Ebola virus titers in infected human macrophages and viral protein synthesis are effectively reduced by silvestrol [1]. Further preliminary work showed that silvestrol has very potent antiviral properties against Zika, corona-, picorna-, chikungunya, and hepatitis E viruses in infected cells without being cytotoxic. The efficacy was already evident at low nanomolar silvestrol concentrations. The expression of viral proteins was strongly inhibited, while cellular proteins were virtually unchanged. This is consistent with the observed low toxicity of silvestrol in primary cells and in various mouse model systems.

Scientific goals: In project A2, we want to investigate the following aspects: (i) Analysis of the antiviral broad-spectrum activity. The viruses that are under investigation include the (+) RNA viruses Zika, hepatitis E (Prof. Hildt), chikungunya, RS (Prof. Schnierle), and Semliki Forest viruses (Prof. Ziebuhr), as well as the (-) - RNA viruses bunya (Prof. Weber), influenza and Lassa (Prof. Ziebuhr). So far, Ebola (cooperation Prof. S. Becker), corona-, rhino- and polioviruses (cooperation of Prof. Ziebuhr) have been identified as being sensitive to silvestrol. (ii) Identification of viral RNA structures and sequence motifs that mediate the silvestrol effect. We will systematically perform mutagenesis and deletion experiments in an established dual luciferase assay. (iii) Toxicity profile of silvestrol. For this purpose, comparative proteomics are performed using SILAC technology (stable isotope labeling by amino acids in cell culture) or label-free MS (cooperation with Dr. Linne). (iv) The helicase eIF4A as a new target for the development of antiviral compounds. Based on computer-assisted drug design, new eIF4A inhibitors, which are readily accessible to chemical synthesis (Prof. Schlitzer collaboration), are characterized.

References A2: 1. Biedenkopf N, Lange-Grünweller K, Schulte FW, Weißer A, Müller C, Becker D, Becker S, Hartmann RK, Grünweller A. The natural compound silvestrol is a potent inhibitor of Ebola virus replication. Antiviral Res. 2016 Nov 15;137:76-81. doi: 10.1016/j.antiviral.2016.11.011.