. Scientific Frontline: Chemically modified plant substances work against the hepatitis E virus

Monday, June 27, 2022

Chemically modified plant substances work against the hepatitis E virus

Chemically modified rocaglamides prevent certain viruses from multiplying.
Credit: Department of Molecular and Medical Virology

Rocaglamides from mahogany plants raise hope for the development of an antiviral drug.

The hepatitis E virus (HEV) is widespread and so far, there is no effective drug. In the search for this, the so-called rocaglamides have come into focus: plant substances that can inhibit the multiplication of viruses. Researchers from the Molecular and Medical Virology Department at the Ruhr University Bochum (RUB) have examined a library of chemically modified rocaglamides for their antiviral effects, which a team from Boston has created. A group of active substances that has a so-called amidino group stood out. It particularly effectively inhibited virus multiplication. The team around Dimas F. Praditya, Mara Klöhn and Prof. Dr. Eike Steinmann reports in the journal Antiviral Research.

Plant substances inhibit the multiplication of cancer cells and viruses

Rocaglamides are a group of plant substances that are produced by various mahogany plants. It is known that they have an inhibitory effect on the multiplication of some cancer cells. It was not until 2008 that findings on their antiviral effects against RNA viruses were published for the first time: for example, they can inhibit the multiplication of Ebolaviruses, HEV, zikaviruses or Sars-Cov-2.

The Boston team around Prof. Dr. John Porco Jr. has created a library of rocaglamids with various chemical changes. "The core structure of the 205 substances is always the same, and chemical groups of different sizes or flexible were attached to it," explains Mara Klöhn. The Bochum group has tested these 205 substances for their effectiveness against HEV in cell culture. The researchers used cancer cell lines and HEV genomes, which are provided with a reporter gene. Based on the amount of protein produced, the blueprint of which is in this reporter gene, you can measure exactly how successfully the virus multiplies in the presence of various substances.

Changed rocaglamides have a stronger effect than natural ones

Dr. Daniel Todt and Mara Klöhn from the team of the Department of Molecular and Medical Virology at RUB in the Botanical Garden, where mahogany plants that produce rocaglamides also thrive.
Credit: Department of Molecular and Medical Virology

The researchers indicate how strongly a substance inhibits the multiplication of viruses by means of a so-called mean inhibitory concentration. The lower it is, the better the substance works. "The mean inhibitory concentration of our three best tested rocaglamides is between 0.5 and 3 nanomolar," reports Mara Klöhn. “For comparison: that of the natural rocaglamide Silvestrol is three to seven nanomolar.“A common feature of the top 3 rocaglamide is an attached amidino group.

Since rocaglamides also have a cell-damaging effect, which is particularly noticeable in cancer cells, the researchers also examined this toxicity in healthy pig liver cells. "The toxicity here was lower than in cell culture, which is based on cancer cell lines," said Mara Klöhn. Further studies would have to investigate the effectiveness and toxicity of the most successful substances tested in the organism. "You could also try to chemically optimize the best amidino rocaglamides so that they have an even greater effect on virus multiplication," she looks optimistically into the future.

The hepatitis E virus is the main cause of acute virus liver inflammation. An estimated 20 million people worldwide fall ill each year, around 70,000 of them die.

Acute infections usually heal on their own in those affected by an intact immune system. HEV can become chronic in people with reduced or suppressed immune systems such as organ transplant recipients or HIV-infected patients. HEV is also particularly threatening for pregnant women. Ribavirin is the only active ingredient in use to date, but it does not work in all cases.

The work was funded by the Federal Ministry of Health (funding code ZMVI1-2518FSB705), the German Center for Infection Research, the Federal Ministry of Education and Research (project Silvir, 16GW0202 and VirBio 01KI2106), and the National Institutes of Health (R35GM118173, U0.

Source/Credit: Ruhr-Universität Bochum (Ruhr University Bochum)


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