Project B1 - Dengue virus, design of inhibitors of the NS3/NS2B-serin protease
Prof. Dr. Wibke Diederich
Department of Pharmaceutical Chemistry
Center of Tumor and Immune Biology
Philipps University Marburg
Tel.: +49 6421 28 25810
Fax: +49 6421 28 26254
- Project description
Background:Infections with dengue virus have reached a record high, with an estimated 50-100 million infections newly occurring worldwide every year. Currently, over one-third of the world’s population lives in endemic areas, mainly in tropical and subtropical regions. However, the vector transmitting the virus has already spread into moderate climatic regions as well.
Dengue virus belongs, like the yellow fever, West Nile, and hepatitis C virus, to the family of Flaviviridae and is transmitted by mosquitoes of the species Aedes aegypti. Clinical symptoms of an infection range from mild to hemorrhagic fever, the latter being fatal for about 22,000 individuals every year, especially children. Because of the lack of specific drugs, treatment is merely symptomatic.
Current drug targets being investigated for their potential to combat this disease include addressing viral entry, RNA replication, and processing, as well as polyprotein processing. In the latter process, the NS3/NS2B-serine protease was shown to be essential for virus maturation. However, up to now only a few micromolar non-peptidic inhibitors have been disclosed.
Following a computer-based approach, the design, synthesis, and biological evaluation of non-covalent, non-peptidic inhibitors of this protease is foreseen. Besides the substrate binding pocket, an allosteric pocket will also be thoroughly investigated. The most promising hits will be optimized with respect to not only their affinity but also their pharmacokinetic properties.