Evaluation of the flavivirus protease as the target for the development of broad-spectrum antivirals against flaviviruses

Vector-borne flaviviruses like dengue, West Nile, yellow fever, Japanese encephalitis, tick-borne encephalitis, and Zika virus are important human pathogens responsible for a high health and economic burden worldwide.

Despite the urgent need, no antivirals for the prevention or treatment of flavivirus infections and mitigation of future outbreaks are currently available.

Pan-flavivirus inhibitors would be extremely valuable as they would allow the treatment of several flavivirus infections with just one pill.

Currently, recombinant proteases from seven different flaviviruses have been produced and studied, however, no one has ever tested protease inhibitors against more than three different flavivirus proteases.

This project aims to assess if the development of broad-spectrum inhibitors of flavivirus protease is feasible and if so to what extent, I. e. how many viruses can be targeted at the same time by one compound.

To achieve this goal a collection of compounds is going to be tested against up to seven different flavivirus proteases using enzymatic assays.

The generated inhibition data will then be used to train machine learning-based models that will allow for the rapid screening of large libraries of compounds in silico and predict their pan-flavivirus activity.

Identified active compounds with broad-spectrum activity will also be used to treat cells infected with different flaviviruses to determine their antiviral activity.