Flavivirus NS2B/NS3 protease: Structure, function, and inhibition

Many flaviviruses are significant human pathogens causing considerable disease burdens, including encephalitis, hemorrhagic fever, and microcephaly, in the regions in which they are endemic. A paucity of treatments for flaviviral infections has driven interest in drug development targeting proteins essential to Flavivirus replication, such as the viral protease. During viral replication, the Flavivirus genome is translated as a single-polyprotein precursor, which must be cleaved into individual proteins by host proteases and a complex of the viral protease, NS3, and its cofactor, NS2B. As this cleavage is an obligate step of the viral life cycle, the Flavivirus protease is an attractive target for antiviral drug development. In this chapter, we will survey the flaviviral protease and recent drug development studies targeting the NS3 active site, as well as studies targeting an NS2B/NS3 interaction site determined from Flavivirus protease crystal structures.