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

DOI: 10.1016/j.antiviral.2009.11.009 DOI Help

Authors: Michela Bollati (University of Milano) , Karin Alvarez (CNRS) , Rene Assenberg (Wellcome Trust Centre for Human Genetics) , Cecile Baronti (Unité des Virus Emergentes, Marseille) , Bruno Carnard (CNRS) , Shelley Cook (The Natural History Museum, London) , Bruno Coutard (CNRS) , Etienne Decroly (CNRS) , Xavier De Lamballerie (Unité des Virus Emergents , Marseille) , Ernest A. Gould (Unité des Virus Emergents , Marseille, Center for Ecology and Hydrology, Oxford) , Gilda Grard (Unité des Virus Emergents , Marseille) , Jonathan Grimes (Division of Structural Biology, University of Oxford) , Rolf Hilgenfeld (University of Lübeck) , Anna M. Jansson (Uppsala University) , Helene Malet (CNRS) , Erika Mancini (University of Oxford) , Eloise Mastrangelo (University of Milano, National Research Center on Nanostructure and BioSystems at Surfaces) , Andrea Mattevij (University of Pavia) , Mario Milani (University Milano) , David I. Stuart (Wellcome Trust Centre for Human Genetics) , Gregory Moureau (Unité des Virus Emergents, Faculté de Médecine) , Johan Neyts (KULeuven - University of Leuven) , Raymond J. Owens (Wellcome Trust Centre for Human Genetics) , Jingshan Ren (University of Oxford) , Barbara Selisko (CNRS) , Silvia Speroni (National Research Center on Nanostructure and BioSystems at Surfaces) , Holger Steuber (University of Lübeck) , Torsten Unge (Uppsala University) , Martino Bolognesi (University of Milano)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Antiviral Research

State: Published (Approved)
Published: November 2009

Abstract: 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.

Journal Keywords: Flavivirus; Flaviviral NS3 protein; Flaviviral NS5 protein; Protease; Helicase; Polymerase; Methyltransferase; Flavivirus protein structure; Antivirals; VIZIER Consortium

Subject Areas: Biology and Bio-materials


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