There are no antiviral agents available to prevent or treat the approximately 96 million symptomatic cases of dengue fever, annually. But the need for new treatments is growing. The disease is caused by the mosquito-borne dengue virus, which is found in nearly all (sub)tropical regions, but especially in Latin America and Asia. The frequency of outbreaks continues to grow, and the virus is expected to impact billions more in the coming decades as the virus spreads to other regions due to climate change and other global trends.
Now, a group from the KU Leuven Rega Institute and Centre for Drug Design and Discovery (CD3) have developed an ultrapotent inhibitor of the dengue virus. The antiviral molecule is exceptionally effective against all known dengue variants and could be used for therapeutic and prevention purposes.
This work is published in Nature in the paper, “A pan-serotype dengue virus inhibitor targeting the NS3–NS4B interaction.”
The highly potent dengue virus inhibitor (JNJ-A07) has a unique mechanism, explained Johan Neyts, PhD, professor of virology at the Rega Institute at KU Leuven. “Together with the research group of Ralf Bartenschlager, PhD, from Heidelberg University, we demonstrated that our inhibitor prevents the interaction between two viral proteins that are part of a kind of copier 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 antiviral exerts nanomolar to picomolar activity against a panel of 21 clinical isolates that, the group reported, “represent the natural genetic diversity of known genotypes and serotypes.” The molecule, they said, reveals a previously undescribed mechanism of antiviral action by preventing the formation of the viral replication complex by blocking the interaction between two viral proteins (NS3 and NS4B), In addition, the antiviral has a high barrier to resistance.
Research in mice suggests that the inhibitor could also be used for prevention purposes. These findings are cause for optimism, as the existing dengue vaccine only offers partial protection.
“Even a low dose of the drug administered via the oral route proved to be very effective,” noted Suzanne Kaptein, PhD, biological group leader at the Rega Institute at KU Leuven. “What is more, the treatment is still effective when the infection is already at its peak. In these cases, the number of virus particles in the blood dropped drastically within 24 hours after the start of the treatment. This goes to show how extremely potent the antiviral drug is.”
“Potent and safe dengue drugs that can be easily taken as tablets could offer anyone effective protection for a certain period of time,” explained Neyts. “Think of people living in areas with an ongoing dengue outbreak, for instance: they could take a dengue drug for a couple of days or weeks. The tablets could also protect travelers or NGO workers during their stay in high-risk regions.”
The antiviral drug will be developed in an easy-to-administer formulation that can be optimized for the treatment and prevention of the disease in dengue-endemic tropical and subtropical regions.
The development of the antiviral was a long haul, said Neyts. “We started this project in 2009. First, we examined many thousands of molecules in a compound library of the CD3 to find one or more molecules that inhibit the virus in lab-grown cells. In other words: we started looking for a needle in a haystack. As soon as we were able to identify such molecules, the medicinal chemists at CD3 could start to work with them. They created many versions of the molecules to boost their efficacy against the virus.”
There are four types of dengue viruses, and the molecule needed to be equally effective against all four of them, added Patrick Chaltin, PhD, managing director, CD3. “It was no easy feat to reach that goal: the optimization process involved about 2,000 steps. Years of intensive collaboration have now resulted in an ultra-potent dengue inhibitor that we are proud to present.”
