Major Breakthrough in Dengue Treatment: Potent Compound JNJ-A07 Shows Efficacy Against All Serotypes

October 7, 2021 /Bio ValleyBIOON/---The dengue virus is a mosquito-borne virus that belongs to a group of viruses known as flaviviruses, for which there are no effective drugs or vaccines. The severe symptoms it causes have earned it the nickname "breakbone fever."

In a new study, researchers from KU Leuven in Belgium, Janssen Pharmaceutica, Heidelberg University in Germany, and Aix-Marseille University in France may have discovered the first-ever treatment for dengue virus infection. Tests in cell cultures and mice demonstrate that a newly identified potent dengue virus inhibitor can effectively inactivate the virus, block its replication, and prevent disease. Whether used prophylactically prior to infection or therapeutically following dengue virus infection, this inhibitor, designated JNJ-A07, appears highly effective at suppressing the virus.The relevant research results were published online in the journal Nature on October 6, 2021, under the title “A pan-serotype dengue virus inhibitor targeting the NS3–NS4B interaction”。

Scott Biering and Eva Harris from the School of Public Health at the University of California, Berkeley published a commentary titled "A step towards therapeutics for dengue" in the journal Nature regarding this study, noting that it represents a significant advance in the field of dengue therapeutics.

The threat posed by the mosquito-borne dengue virus is undeniable. With an estimated at least 98 million infections annually, it is endemic in 128 countries worldwide. The virus can cause severe flu-like symptoms and may sometimes progress to severe dengue, a potentially fatal condition.

Because the dengue virus has four distinct serotypes, infection with one does not confer cross-protection against the others, and a secondary infection is often more severe. To date, a dengue vaccine named Dengvaxia has only been approved for use in some countries and is effective against a single serotype.

Unprecedented

The unassuming JNJ-A07 was discovered through the screening of tens of thousands of potential candidate compounds, a process that co-corresponding author Johan Neyts described as “looking for a needle in a haystack.” The effort proved worthwhile. Neyts stated that its efficacy in infected animals is unprecedented, demonstrating significant antiviral activity even when treatment is initiated at the peak of viral replication.

JNJ-A07 exerts its effect by targeting the interaction between two proteins—NS3 and NS4B—that are essential for dengue virus replication. Tests conducted in cells derived from mosquitoes and humans demonstrated its efficacy against all four dengue virus strains.

Given the dengue virus's capacity for rapid evolution, the authors also investigated how JNJ-A07 would perform in the event of viral mutation. Neyts stated, "In the laboratory, within infected cells, it took nearly six months for the virus to develop significant resistance to this compound. Given such a high barrier to resistance, this is unlikely to become a clinical concern."

JNJ-A07 exhibits high specificity for the dengue virus, image from Nature, 2021, doi:10.1038/s41586-021-03990-6.

Intriguingly, the mutations conferring resistance also appear to prevent the virus from replicating in mosquito cells. This may suggest that even if the virus develops resistance to JNJ-A07 treatment, it would no longer be transmitted by mosquitoes, effectively reaching a dead end within the host.

OngoingClinical trial

Reassuringly, whether administered to mice before or after infection, compound JNJ-A07 effectively inhibited dengue virus infection. Neyts said that the compound has now been "further optimized" and is currently under clinical development by Johnson & Johnson.

Biering and Harris wrote that several questions regarding JNJ-A07 remain, including whether it would be more effective when used in combination with other compounds. Another potential concern is whether it could increase susceptibility to reinfection. When individuals are infected with the dengue virus, its presence in the blood—known as viremia—typically stimulates a robust immune response that protects them from future reinfections. However, in some individuals, a weaker immune response renders them susceptible to reinfection with a different strain, which can lead to more severe symptoms.

Given that JNJ-A07 functions by reducing viremia, Biering and Harris cautioned that further research is needed to verify whether this might make individuals more susceptible to reinfection.

Despite the unknown factors, Neyts said the study offers exciting possibilities. He said, "It is truly amazing to see how effective this compound is in animals," and described the research as "a remarkable journey." (Bioon.com)

References:

Suzanne J. F. Kaptein et al. A pan-serotype dengue virus inhibitor targeting the NS3–NS4B interaction. Nature, 2021, doi:10.1038/s41586-021-03990-6.

Scott B. Biering et al. A step towards therapeutics for dengue. Nature, 2021, doi:10.1038/d41586-021-02638-9.