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A New Dengue antiviral that is extremely effective.

Researchers from the KU Leuven Rega Institute and CD3 have created an ultrapotent inhibitor of the dengue virus, which causes dengue fever. Janssen Pharmaceutica, N.V. cooperated closely with the teams. The antiviral compound is highly efficient against all known dengue strains and could be utilized for both treatment and prevention. The findings were published in Nature by the two teams.

Dengue fever infects up to 400 million people each year, sickens 100 million, and kills thousands. A high fever and significant muscle and joint pain are among the disease's symptoms. Some patients also have capillary leakage or subcutaneous hemorrhage.

The mosquito-borne dengue virus causes the disease, which can be found in practically all (sub)tropical locations, but mainly in Latin America and Asia. The frequency of outbreaks is increasing, and the virus is anticipated to affect billions more people in the next decades as it spreads to other parts of the world as a result of climate change and other global trends. Dengue fever was already on the World Health Organization's list of ten global health hazards in 2019.

There are currently no antiviral medications available to prevent or treat dengue fever. This could change thanks to a breakthrough finding conducted by Johan Neyts (Rega Institute at KU Leuven) and Patrick Chaltin (CD3/CISTIM Leuven vzw) and carried out in collaboration with a team lead by Marnix van Loock (Janssen Pharmaceutica, N.V.).

Professor Johan Neyts of the Rega Institute at KU Leuven says that the antiviral has a unique mechanism. "We proved that our inhibitor blocks the interaction between two viral proteins that are part of a kind of copier for the virus's genetic information," says Professor Ralf Bartenschlager of Heidelberg University. If this contact is disrupted, the virus will be unable to replicate its genetic material. No new virus particles are created as a result."

The scientists demonstrated that the antiviral is particularly efficient against all known dengue virus strains in collaboration with Professor Xavier de Lamballerie (Aix-Marseille University).

The inhibitor was also tried on mice by the researchers. Suzanne Kaptein (KU Leuven's Rega Institute): "Even a little dose of the medicine taken orally was found to be extremely beneficial.

Furthermore, even when the infection has reached its peak, the treatment is still beneficial. The quantity of virus particles in the blood in these patients fell dramatically within 24 hours of starting treatment. This demonstrates how effective the antiviral medication is."

According to research done on mice, the inhibitor could also be utilized to prevent disease. These findings are encouraging, given that the current dengue vaccine only provides partial protection.

KU Leuven Professor Johan Neyts: "Dengue medications that are both potent and safe and can be administered as tablets could provide excellent protection for anybody for a set amount of time.

Consider persons who live in locations where a dengue outbreak is ongoing: they could take a dengue medicine for a few days or weeks. The tablets could also provide protection to travelers or NGO employees in high-risk areas."

The antiviral medicine will be produced in a simple-to-use formulation that may be tailored to treat and prevent dengue fever in dengue-endemic tropical and subtropical areas.

Professor Johan Neyts says it took a long time to develop the antiviral (KU Leuven). "We began working on this project in 2009. First, we looked through a compound library at the Centre for Drug Design and Discovery (CD3) to see if there were any compounds that could stop the virus from infecting lab-grown cells. To put it another way, we began looking for a needle in a haystack. The medicinal chemists at CD3 could begin working with these substances as soon as we were able to identify them. To increase their potency against the virus, they synthesized several variants of the molecules."

According to Patrick Chaltin of the Centre for Drug Design and Discovery, there are four varieties of dengue viruses, and the molecule must be equally efficient against all four. "It wasn't an easy task to achieve that goal: the optimization procedure included almost 2000 steps. Years of hard work have paid off in the form of an ultra-effective dengue inhibitor, which we are happy to share."

Since 2013, Janssen Pharmaceutica scientists such as Marnix Van Loock, Olivia Goethals, and Tim Jonckers have worked closely with the KU Leuven researchers to accelerate the chemical series' development.

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