KU Leuven: KU Leuven develops very powerful antiviral agent against dengue

Every year about 400 million people become infected with dengue. Of them, about 100 million people get sick, and thousands do not survive dengue. Symptoms of the disease include a high fever and severe muscle and joint pain. Some patients also develop subcutaneous bleeding or leaky capillaries.

The disease is caused by the mosquito-borne dengue virus, which occurs in almost all tropical and subtropical regions, but mainly in Latin America and Asia. Outbreaks are becoming more frequent. The virus is expected to affect billions more people in the coming decades as it spreads to other regions due to climate change and other global trends. In 2019, the World Health Organization already included dengue in its list of ten threats to global health.

There are currently no antivirals available to prevent or treat dengue. This may change thanks to the groundbreaking discovery of teams led by Johan Neyts (Rega Institute, KU Leuven) and Patrick Chaltin (CD3/CISTIM Leuven vzw), which continued in collaboration with a team led by Marnix van Loock at our strategic partner Janssen Pharmaceutica, NV

Block the virus’s ‘copier’
The antiviral drug has a unique mechanism, says Professor Johan Neyts of the Rega Institute at KU Leuven. “Together with the research group of Professor Ralf Bartenschlager from the University of Heidelberg, we have shown that our virus inhibitor prevents the interaction between two viral proteins that are part of a kind of copying machine for the genetic material of the virus. If this interaction is blocked, the virus can no longer copy its genetic material. As a result, no new virus particles are produced.”

The optimization process consisted of about 2000 steps. Years of intensive cooperation has now resulted in an extremely powerful dengue inhibitor that we are proud to present.

– Patrick Chaltin (CD3)

Together with Professor Xavier de Lamballerie (University of Aix-Marseille), the team proved that the antiviral drug is highly effective against all known variants of the dengue virus.

The researchers also tested the inhibitor on mice. Suzanne Kaptein (Rega Institute, KU Leuven): “Even a low, orally administered dose of the drug proved to be very effective. Moreover, the treatment is still effective when the infection is already at its peak. In those cases, the number of virus particles in the blood drastically within 24 hours of starting treatment, demonstrating how extremely potent the antiviral is.”

Also suitable for prevention
Research in mice suggests that the inhibitor can also be used preventively. These findings are cause for optimism, as the existing dengue vaccine offers only partial protection.

Professor Johan Neyts (KU Leuven): “Potent and safe drugs against dengue that can easily be taken as a tablet can offer everyone effective protection for a certain period of time. Think, for example, of people living in areas where there is an outbreak of dengue. is: They could take a dengue drug for a few days or weeks. The tablets could also protect travelers or NGO workers while staying in high-risk areas.”

The antiviral agent will be developed in an easy-to-administer formulation that can be optimized for the treatment and prevention of the disease in tropical and subtropical regions where dengue is endemic.

Search of many years
The development of the antiviral drug was a long-term task, says Professor Johan Neyts (KU Leuven). “We started this project in 2009. First we examined many thousands of molecules in a so-called compound library of the Center for Drug Design and Discovery (CD3) to find one or more molecules that inhibit the virus in cells grown in laboratory. In other words, we went looking for a needle in a haystack. Once we identified such molecules, our CD3 colleagues could get to work, making different versions of the molecules to increase their effectiveness against the virus.”

There are four types of dengue viruses, and the molecule had to be equally effective against all four, says Patrick Chaltin of the Center for Drug Design and Discovery . “It was no easy task to achieve that goal: the optimization process consisted of about 2000 steps. Many years of intensive cooperation has now resulted in an extremely powerful dengue inhibitor that we are proud to present.”

Since 2013, scientists from Janssen Pharmaceutica – including Marnix Van Loock, Olivia Goethals and Tim Jonckers – have been working closely with the KU Leuven teams to accelerate the further development of the chemical series.

Ambitions beyond dengue
KU Leuven and CD3 also have ambitious plans for the fight against other viruses. Among other things, they are looking for broad-spectrum antivirals against coronaviruses, but the ambitions reach even further. Patrick Chaltin: “In the future we want to develop a series of antiviral molecules against the different virus families with pandemic potential, not just against coronaviruses. For this we need significant financial resources, which we are now trying to acquire.”

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