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Entry from: 02.05.2017
Category: News, Press Releases

New inhibitors curb influenza viruses

Influenza viruses can be dangerous for humans. For this reason, scientists have been looking for ways of stopping this viral infection. Multivalent inhibitors, which bind to the surface of the virus with the aid of numerous ligands, appear to be particularly promising here. Scientists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), the Humboldt-Universität zu Berlin (HU), the Charité, the German Rheumatism Research Centre Berlin (DRFZ) and the Freie Universität Berlin (FU) have now for the first time combined the multivalent approach with peptides from antibodies. Their approach was successful: In-vitro and in-vivo experiments have shown that influenza A viruses can be reliably inhibited with the new active substance. The new inhibitor design paves the way for the development of new antiviral medications, and not just against influenza but also against other viral infections. The results of the study have just appeared in the highly acclaimed specialist journal "Angewandte Chemie".

Elektronenmikroskie- Aufnahmen zeigen die Bindung der neuen Inhibitoren an Influenza-Viren. Bildautoren: Kai Ludwig/Maria Glanz

Influenza viruses are tricky. When we breathe in they pass into our lungs, where they attack the pulmonary epithelial cells, the first and decisive step in an infection by these viruses. The attack is possible, because the viruses bind to certain host cells in the lungs. It is precisely this step that scientists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and the Humboldt Universität zu Berlin (HU) want to block. Together with colleagues from the Charité, the German Rheumatism Research Centre Berlin (DRFZ) and the Freie Universität Berlin (FU), the researchers have therefore set off in search of an active substance that inhibits influenza viruses, even if the infection has already broken out. Up to now, antiviral therapies have not been capable of this. But after more than two and a half years of research across all institutes, the ice in basic research appears to have been broken.
"We have delivered the proof of principle that influenza viruses can be excellently inhibited with our approach," says Prof. Dr. Christian Hackenberger, Section Head at the FMP and Professor of Chemical Biology at the Humboldt-Universität. "We have thus opened up completely new avenues for clinical experiments."


Nature inspired binding sites
In active substance development, the researchers fell back on so-called multivalent inhibitors. In this case, it was a question of nanoparticles that carry numerous ligands on their surface, which bind very specifically to the flu virus. As a result of the large number of bonds, there is a much greater chance that the virus can be identified and taken out of play. The multivalent approach with sialic acid ligands has been amply described in the literature. "By adopting a new strategy, in which we use peptides as ligands, we were able to produce new inhibitors, which offer considerable scope for chemical synthesis," says Maria Glanz, chemist at the FMP.
In the case of influenza, the immune system produces antibodies against the virus, a process that is also exploited every year in flu vaccination. In preliminary work, the researchers had identified the regions of the antibodies that recognise the virus. The decisive sites were then cut out and synthesised by Maria Glanz at the FMP. The peptide sequences adapted from nature were then mounted on the inhibitor as ligands, and that was done in enormous numbers. "This makes the affinity to the virus much greater, in other words the bond is stronger," stresses Prof. Dr. Andreas Herrmann, Head of the Molecular Biophysics section at the HU. This was also confirmed in the experiments: "In-vitro, our multivalent peptide-nanoparticle conjugates were really effective."

Proof of principle delivered in vitro
The experiments with the new inhibitor were successfully conducted on model membranes and on human cell cultures. The inhibition of the influenza viruses also functioned in the mouse model, which among other things could be measured in terms of the loss or maintenance of body weight. However, here the antiviral effect declined after four days, as the animals were only given the active substance one single time. "We only treated the animals once, in order to spare them from additional stress," explains Daniel Lauster, biologist at the HU Institute for Molecular Biophysics. "A repeated dose of the active substance, as is standard practice in the case of other medications, would undoubtedly have had longer lasting effects."
As the next step, the researchers want to optimise the concept for further applications. However, research already has a completely new inhibitor design at its disposal, which can be used in future for the development of new binding inhibitors.


New class of molecules is incredibly adaptable
According to the researchers, the new class of molecules can adapt much more easily to the natural variants of the virus, as they are based on different designs. This is important, because virus proteins can change structurally. Previous systems were, in contrast, always only targeted against one binding site on the virus. "Now, we have far more options and can adapt our system much more easily, for instance when resistances and mutants occur," explains Daniel Lauster. Further advantages are that the new inhibitor design is also suitable for other peptide systems and that it is very easy to synthesize.
"The truly new thing about this concept is the combination of a multivalent inhibitor and very short antibody fragments," says Christian Hackenberger to sum up the results. Although proof was delivered on influenza A viruses, it can also be transferred to other viral infections. Biophysicist Andreas Herrmann, who is also speaker of the successful IRI Life Sciences at the HU, adds: "The project shows once more how well positioned we are in terms of basic research in Berlin and what fruits co-operation between university and non-university institutions can bear."
Five large Berlin research institutions from the field of life science were involved in this research project: The Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), the Institute for Biology, Molecular Biophysics, IRI Life Sciences of the Humboldt-Universität zu Berlin (HU), the Charité – Universitätsmedizin, the German Rheumatism Research Centre Berlin (DRFZ) and the Institute for Chemistry and Biochemistry – Organic Chemistry at the Freie Universität Berlin (FU). The Deutsche Forschungsgemeinschaft (DFG) funded the project within the context of the Collaborative Research Centre SFB 765 "Multivalency as a chemical organisation and action principle: New architectures, functions and applications".


doi.org/10.1002/anie.201702005

 

Contact
Prof. Dr. Christian Hackenberger
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
hackenbe (at) fmp-berlin.de
Tel.: 0049 30 94793-181

Silke Oßwald
Öffentlichkeitsarbeit/Public Relations
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
osswald (at) fmp-berlin.de
Tel.: 0049 30 94793-104


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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
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