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Polymerases of hepatitis C viruses and flaviviruses: Structural and mechanistic insights and drug development

Shi, Pei-Yong and Caillet-Saguy, Célia and Julien, Lescar and Stéphane , Bressanelli (2014) Polymerases of hepatitis C viruses and flaviviruses: Structural and mechanistic insights and drug development. Antiviral research.

Abstract

The family Flaviviridae comprises several major human pathogens including Hepatitis C virus (HCV, genus hepacivirus), Yellow Fever virus, West-Nile virus or Dengue virus (genus flavivirus). The Flaviviridae genomes comprise a single stranded RNA segment encoding a single polyprotein that is subsequently processed into ten mature viral proteins. The non-structural proteins are released from the C-terminus of the polyprotein and contribute to the infectious cycle by forming membrane-bound multi-protein compartments within host cells, named the replication complexes, where transcription and replication of the viral genome takes place. Two non-structural proteins are endowed with multiple enzymatic activities and represent important targets against which specific antiviral inhibitors have been developed. X-ray crystal structures of these viral enzymes as well as in-depth understanding of the molecular basis of their activities have contributed tremendously to the development of antiviral compounds, currently approved or in advanced clinical trials for HCV treatment. One of the prime targets is the RNA-dependent RNA polymerase (RdRp, NS5B for HCV, NS5 for flaviviruses). Here we review our current knowledge of the structural basis for viral RNA synthesis by NS5B and NS5. These data both offer perspectives for further drug design and constitute major advances in our basic understanding of viral RdRp. They thus point to future research directions in the field.

Item Type: Article
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/21041

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