Immunostaining of three proteins (in blue, red and green) from hepatitis C virus that replicates within the cytoplasm of an infected cell. Such microscopy studies, which were done at the PLATIM of the SFR biosciences, allows studying in details the mode of action of direct-acting antivirals on viral replication. Bertrand Boson Inserm?
The team "Enveloped viruses, vectors & immunotherapy" led by François-Loïc Cosset of the Centre international de recherche en infectiologie ( CIRI ), discovered one of the modes of action of Daclatasvir,a novel inhibitor of hepatotis C virus (HCV), targeting the NS5A protein. This study was published in Decembre 5th, 2016 in Gastroenterology.
Daclatasvir is a direct-acting antiviral agent and potent inhibitor of NS5A, which is involved in replication of HCV genomes, presumably via membranous web shaping, and assembly of new virions, likely via transfer of the HCV RNA genome to viral particle assembly sites. Daclatasvir inhibits the formation of new membranous web structures and, ultimately, of replication complex vesicles, but also inhibits an early assembly step. The team has investigated the relationship between daclatasvir-induced clustering of HCV proteins, intracellular localization of viral RNAs and inhibition of viral particle assembly.
In addition to inhibiting replication complex biogenesis, the team has discovered that daclatasvir prevents viral assembly by blocking transfer of the viral genome to assembly sites. This leads to clustering of HCV proteins, because viral particles and replication complex vesicles cannot form and/or egress. This dual mode of action of daclatasvir could explain its highly potent efficacy in blocking HCV replication in cultured cells and in treatment of patients infected with HCV.
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This work was supported by the French ‘Agence Nationale de la Recherche sur le SIDA et les hépatites virales’ (ANRS), the European Research Council (ERC-2008-AdG-233130-HEPCENT) and the LabEx Ecofect (ANR-11-LABX-0048).
References : Daclatasvir Prevents Hepatitis C Virus by Blocking Transfer of Viral Genome to Assembly Sites. Bertrand Boson, Solène Denolly, Fanny Turlure, Christophe Chamot, Marlène Dreux, François-Loïc Cosset;