Hepatitis C virus NS5A: enigmatic but still promiscuous 10 years on!

作者: Douglas Ross-Thriepland , Mark Harris

DOI: 10.1099/JGV.0.000009

关键词: Viral life cycleNS3NS5BViral replicationNS5AViral proteaseGenomeBiologyVirologyHepatitis C virus

摘要: Since one of us co-authored a review on NS5A decade ago, the hepatitis C virus (HCV) field has changed dramatically, primarily due to advent JFH-1 cell culture infectious clone, which allowed study all aspects life cycle from entry exit. This will describe advances in our understanding biology over past decade, highlighting how system determine that is essential not only genome replication but also assembly virions. We shall recent structural insights - predicted comprise three domains; X-ray crystallography revealed structure domain I there lack detailed information about other two domains, are be largely unstructured. Recent into phosphorylation discussed, and we highlight few pertinent examples ever-expanding list NS5A-binding partners identified decade. Lastly, literature showing potential target for new class highly potent small molecules function inhibit replication. These direct-acting antivirals (DAAs) now either licensed, or late stages approval clinical use both USA UK/Europe. In combination with DAAs targeting viral protease (NS3) polymerase (NS5B), they revolutionizing treatment HCV infection.

参考文章(84)
Sulyi Kim, Tomoko Date, Hiroshi Yokokawa, Tamaki Kono, Hideki Aizaki, Patrick Maurel, Claire Gondeau, Takaji Wakita, Development of hepatitis C virus genotype 3a cell culture system Hepatology. ,vol. 60, pp. 1838- 1850 ,(2014) , 10.1002/HEP.27197
Sebastian M. Lambert, David R. Langley, James A. Garnett, Richard Angell, Katy Hedgethorne, Nicholas A. Meanwell, Steve J. Matthews, The crystal structure of NS5A domain 1 from genotype 1a reveals new clues to the mechanism of action for dimeric HCV inhibitors Protein Science. ,vol. 23, pp. 723- 734 ,(2014) , 10.1002/PRO.2456
Dries Verdegem, Aurélie Badillo, Jean-Michel Wieruszeski, Isabelle Landrieu, Arnaud Leroy, Ralf Bartenschlager, François Penin, Guy Lippens, Xavier Hanoulle, Domain 3 of NS5A Protein from the Hepatitis C Virus Has Intrinsic α-Helical Propensity and Is a Substrate of Cyclophilin A Journal of Biological Chemistry. ,vol. 286, pp. 20441- 20454 ,(2011) , 10.1074/JBC.M110.182436
Simon Reiss, Christian Harak, Inés Romero-Brey, Danijela Radujkovic, Rahel Klein, Alessia Ruggieri, Ilka Rebhan, Ralf Bartenschlager, Volker Lohmann, The Lipid Kinase Phosphatidylinositol-4 Kinase III Alpha Regulates the Phosphorylation Status of Hepatitis C Virus NS5A PLoS Pathogens. ,vol. 9, pp. e1003359- ,(2013) , 10.1371/JOURNAL.PPAT.1003359
François Penin, Volker Brass, Nicole Appel, Stephanie Ramboarina, Roland Montserret, Damien Ficheux, Hubert E. Blum, Ralf Bartenschlager, Darius Moradpour, Structure and Function of the Membrane Anchor Domain of Hepatitis C Virus Nonstructural Protein 5A Journal of Biological Chemistry. ,vol. 279, pp. 40835- 40843 ,(2004) , 10.1074/JBC.M404761200
Timothy L. Tellinghuisen, Katie L. Foss, Jason Treadaway, Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. PLOS Pathogens. ,vol. 4, ,(2008) , 10.1371/JOURNAL.PPAT.1000032
Mair Hughes, Stephen Griffin, Mark Harris, Domain III of NS5A contributes to both RNA replication and assembly of hepatitis C virus particles. Journal of General Virology. ,vol. 90, pp. 1329- 1334 ,(2009) , 10.1099/VIR.0.009332-0