Dengue virus protease

Infectious Diseases: Dengue Virus NS2B-NS3 Protease Inhibitors

Stefan Hammerschmidt, Hannah Maus

Mosquitoes are the vectors of several severe diseases. Due to increased trade, travel behavior, and climate change, there is a worldwide spread of Aedes aegypti, the transmitter of Dengue, Zika, West Nile and Yellow fever, which are caused by single- stranded RNA viruses of the family of flaviviridae.

The flaviviral heterodimeric serine protease NS2B-NS3, consisting of the NS3 protease domain and the NS2B co-factor, is essential for Dengue and Zika virus maturation and replication in host cells. Its inhibition abolishes virus replication. Therefore, the protease represents a promising drug target for the treatment of these neglected diseases. So far, no rational therapy for DENV and ZIKV infections are approved.

Beyond designing new allosteric inhibitors, we investigate the interaction between the inhibitors and the protease by crystallization, MST, switchSENSE, NMR, smFRET, ITC and PAL. Furthermore, we address biochemical issues with respect to autocatalytic fragmentation as well as the conformational flexibility of these proteases.

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