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

• Published in: Antiviral research 2010-08, Vol.87 (2), p.125-148
• Main Authors: Bollati, Michela, Alvarez, Karin, Assenberg, René, Baronti, Cécile, Canard, Bruno, Cook, Shelley, Coutard, Bruno, Decroly, Etienne, de Lamballerie, Xavier, Gould, Ernest A., Grard, Gilda, Grimes, Jonathan M., Hilgenfeld, Rolf, Jansson, Anna M., Malet, Hélène, Mancini, Erika J., Mastrangelo, Eloise, Mattevi, Andrea, Milani, Mario, Moureau, Grégory, Neyts, Johan, Owens, Raymond J., Ren, Jingshan, Selisko, Barbara, Speroni, Silvia, Steuber, Holger, Stuart, David I., Unge, Torsten, Bolognesi, Martino
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antivirals; Biologi; Biology; Biomedical Research - organization & administration; Biomedical Research - trends; Cell and molecular biology; Cell- och molekylärbiologi; Communicable Diseases, Emerging - epidemiology; Communicable Diseases, Emerging - virology; Dengue virus; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes - chemistry; Enzymes - genetics; Enzymes - metabolism; European Union; Flaviviral NS3 protein; Flaviviral NS5 protein; Flaviviridae; Flavivirus; Flavivirus - drug effects; Flavivirus - enzymology; Flavivirus Infections - epidemiology; Flavivirus Infections - virology; Flavivirus protein structure; Helicase; Humans; Methyltransferase; NATURAL SCIENCES; NATURVETENSKAP; Polymerase; Protease; Review; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; Virus Replication - drug effects; VIZIER Consortium; West Nile virus; Yellow fever virus
• ISSN: 0166-3542; 1872-9096; 1872-9096
• DOI: 10.1016/j.antiviral.2009.11.009

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.