Würzburg scientists are working on the development of new drugs to fight monkeypox

Poxviruses pose a threat to humanity that must be taken seriously, as demonstrated by the current outbreak of monkeypox. A research team from the University of Würzburg is currently working on the development of new drugs.

The coronavirus pandemic is far from over, and already another virus is causing a stir: “International monkeypox outbreak” was the cry of the media a few weeks ago, followed by daily headlines like “first case of monkeypox in Baden – Württemberg, Bavaria, Berlin and so on”. Later reports, such as that of the Bavarian public broadcaster Bayerischer Rundfunk – “Study: monkeypox pathogen mutates faster than expected” – or that of the German weekly Der Spiegel – “The doctor says about monkeypox: ‘We are past the point where the virus could still have been stopped completely'”, did nothing to calm the situation.

And no later than since the World Health Organization (WHO) declared the monkeypox outbreak in more than 50 countries an “emergency of international concern” on July 23, it should be clear to everyone: the viruses can cross species barriers at any time and cause new diseases, called zoonoses, in humans. In extreme cases, they can even trigger another pandemic.

Innovative approaches to drug development

In this context, it seems more than fitting that the University of Würzburg (JMU) is now starting a new research project that deals with this topic. “A structure-based approach to combating zoonotic poxviruses” is its title.

This project, with funding of around 700,000 euros from the Volkswagen Foundation, is led by Professor Utz Fischer, holder of the JMU Chair of Biochemistry, and his colleague Dr Clemens Grimm. Also on board is Intana Bioscience GmbH, a biotechnology company based near Munich with a particular interest in the development of new agents. Poxviruses are the focus of this project.

Poxviruses have high risk potential

“We know that animals carry many types of viruses in their bodies that can pose a threat to humans,” says Utz Fischer. Unfortunately, it is impossible to predict which of them will be the next to cross species barriers. However, it is clear that some viruses have a higher potential than others and are therefore more threatening to humanity, with poxviruses topping the list. The objective of the project is therefore to design new approaches to develop new drugs against smallpox pathogens. For this, scientists are looking for substances that interfere with the process of viral transcription and thus prevent viruses from multiplying.

Fischer and his team can build on the findings they presented to the public last fall. “We succeeded in visualizing the poxviral gene expression machinery at the atomic level”, explains the biochemist. These studies therefore make it possible to observe how the molecular machinery acts when the virus multiplies. The images show in detail the functioning of the actors involved during the first phase of transcription. The short videos can be viewed on the university’s YouTube channel:

An approach that can also be applied to swine fever

With the search for agents capable of inhibiting these molecular machines, the team can exploit a particular circumstance: while many viruses draw heavily on the biochemical resources of the host cell for their multiplication, poxviruses encode their own molecular machinery in their genome for this purpose. The important components of this machinery are two enzymes: DNA polymerase, which multiplies viral genes, and RNA polymerase, which transcribes viral genes into mRNA.

This unique replication strategy provides the opportunity to search for inhibitors of key viral complexes and enzymes that attack at this precise point and thus spare host cells, ideally making them free of side effects. If the team succeeds in identifying and designing such molecules, they could even kill two birds with one stone: “Because the transcription mechanisms of Poxviridae and Asfarviridae are very similar, our research is also likely to be relevant for the economically highly threatening Asfarvirus disease linked to swine fever,” says Fischer.

Technical progress helps research

What is most helpful to scientists in their work are technical advances. One of them is a significant increase in the resolution of cryo-electron microscopic images. Using this technology, samples are “instantly frozen” at temperatures down to minus 180 degrees Celsius. This is what makes it possible to examine molecules and biological complexes in solution and to reconstruct their three-dimensional structure on the scale of atoms.

The JMU has had a suitable electron microscope for many years. “Many medically relevant target molecules therefore become central to drug design. We will use this technology alongside established methods to identify molecules that target the particular structures of poxviruses and disrupt their multiplication,” explains Clemens Grimm, who performs structural biology analyzes at the department.

Indeed, the scientists involved are optimistic that in the coming years they will succeed in defining a number of chemical compounds that can serve as a sort of guiding structure for the further development of a pharmaceutical product.

Poxviruses are a threat for several reasons

It is, of course, a coincidence that the research team begins its work at the same time as this outbreak of monkeypox – the app was written months ago. But what is no coincidence is that scientists are focusing on poxviruses. After all, these pose a potential threat to humanity for a variety of reasons. For one thing, there are currently very few antiviral drugs available, and these often display very limited potency.

Additionally, although there is effective protection against smallpox infection in the form of vaccination, after the World Health Organization (WHO) declared smallpox eradicated in 1980, corresponding vaccination campaigns were discontinued in subsequent years. Since then, herd immunity against poxviruses has declined significantly in humans. No wonder a recent study ranks the monkeypox virus among the most threatening viruses due to the risk of infecting humans, adapting to its new host through mutations and then spreading exponentially. .

Source:

Julius-Maximilians-Universität Würzburg, JMU

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