Dengue virus (DENV) is a virus transmitted by mosquitos that has spread to more than 130 countries in tropical and subtropical regions of the world. All four serologically different DENV are responsible for around 390 million infections, annually. While the majority of DENV infections cause a mild acute febrile illness called dengue, approximately 500,000 cases every year develop a severe dengue with potentially deadly consequences. Nearly half of the global population is currently exposed to the virus and due to global, environmental and economic factors (e.g. rising temperatures, increasing urbanization, and intercontinental travels), the frequency and the global distribution of DENV infections are expected to further grow in the future. Although DENV represents a major threat to global public health, no specific treatments or a fully protective and safe vaccine are available to treat and prevent DENV infections, highlighting the urgent need for developing new antiviral agents able to tackle this virus.
The identification of molecules able to block specific and critical viral targets would clearly have an enormous impact on society. Indeed, antiviral drugs would dramatically decrease the global disease burden of dengue by essentially preventing the deadly complications and reducing the mortality rate of DENV infections. As a consequence, the availability of effective therapeutic options for DENV would also have a profound economic benefit as it will help to reduce the huge economic losses due to the costs incurred for hospitalisation and supportive care, mostly in low/middle-income countries.
This project is focused on the early stages of the drug development and the main objective of FINDER is the development of innovative and effective anti-DENV therapeutic options able to disrupt the interaction between the viral NS3 and NS5 proteins, which play a key role in the viral replication. Since this target is highly conserved among the different DENV serotypes, the inhibition of this interaction by small molecules may represent a promising strategy for the development of drugs with efficacy against all DENV. Moreover, this class of compounds could be less prone to induce resistance as increasing evidence suggests that dissociative inhibitors of protein-protein interactions possess a high barrier to drug resistance. Overall, this project led to the identification of antiviral compounds acting by disrupting the NS3-NS5 interaction, paving the way for the development of a new class of selective anti-DENV agents.
