Structure and functionality in flavivirus NS-proteins: perspectives for drug design

Flaviviridae are small enveloped viruses hosting a positive-sense single-stranded
RNA genome. Besides yellow fever virus, a landmark case in the history of
virology, members of the Flavivirus genus, such as West Nile virus and dengue
virus, are increasingly gaining attention due to their re-emergence and incidence
in different areas of the world. Additional environmental and demographic
considerations suggest that novel or known flaviviruses will continue to emerge
in the future. Nevertheless, up to few years ago flaviviruses were considered low
interest candidates for drug design. At the start of the European Union VIZIER
Project, in 2004, just two crystal structures of protein domains from the
flaviviral replication machinery were known. Such pioneering studies, however,
indicated the flaviviral replication complex as a promising target for the
development of antiviral compounds. Here we review structural and functional
aspects emerging from the characterization of two main components (NS3 and NS5
proteins) of the flavivirus replication complex. Most of the reviewed results
were achieved within the European Union VIZIER Project, and cover topics that
span from viral genomics to structural biology and inhibition mechanisms. The
ultimate aim of the reported approaches is to shed light on the design and
development of antiviral drug leads.