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.
Bollati
Michela
M
Department of Biomolecular Sciences and Biotechnology, University of Milano, Via Celoria 26, 20133 Milano, Italy.
Alvarez
Karin
K
Assenberg
René
R
Baronti
Cécile
C
Canard
Bruno
B
Cook
Shelley
S
Coutard
Bruno
B
Decroly
Etienne
E
de Lamballerie
Xavier
X
Gould
Ernest A
EA
Grard
Gilda
G
Grimes
Jonathan M
JM
Hilgenfeld
Rolf
R
Jansson
Anna M
AM
Malet
Hélène
H
Mancini
Erika J
EJ
Mastrangelo
Eloise
E
Mattevi
Andrea
A
Milani
Mario
M
Moureau
Grégory
G
Neyts
Johan
J
Owens
Raymond J
RJ
Ren
Jingshan
J
Selisko
Barbara
B
Speroni
Silvia
S
Steuber
Holger
H
Stuart
David I
DI
Unge
Torsten
T
Bolognesi
Martino
M
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D035843:Biomedical Research / Q000458:organization & administration / Q000639:trends; D021821:Communicable Diseases, Emerging / Q000453:epidemiology / Q000821:virology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004798:Enzymes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005062:European Union; D005416:Flavivirus / Q000187:drug effects / Q000201:enzymology*; D018177:Flavivirus Infections / Q000453:epidemiology / Q000821:virology; D006801:Humans; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D004798:Enzymes; D017361:Viral Nonstructural Proteins