title: Antiviral activity and mode of action of TMC647078, a novel nucleoside inhibitor of the hepatitis C virus NS5B polymerase.
abstract: Chronic infection with hepatitis C virus (HCV) is a major global health burden and is associated with an increased risk of liver cirrhosis and hepatocellular carcinoma. Current therapy for HCV infection has limited efficacy, particularly against genotype 1 virus, and is hampered by a range of adverse effects. Therefore, there is a clear unmet medical need for efficacious and safe direct antiviral drugs for use in combination with current treatments to increase cure rates and shorten treatment times. The broad genotypic coverage achievable with nucleosides or nucleotides and the high genetic barrier to resistance of these compounds observed in vitro and in vivo suggest that this class of inhibitors could be a valuable component of future therapeutic regimens. Here, we report the in vitro inhibitory activity and mode of action of 2'-deoxy-2'-spirocyclopropylcytidine (TMC647078), a novel and potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase that causes chain termination of the nascent HCV RNA chain. In vitro combination studies with a protease inhibitor resulted in additive efficacy in the suppression of HCV RNA replication, highlighting the potential for the combination of these two classes in the treatment of chronic HCV infection. No cytotoxic effects were observed in various cell lines. Biochemical studies indicated that TMC647078 is phosphorylated mainly by deoxycytidine kinase (dCK) without inhibiting the phosphorylation of the natural substrate, and high levels of triphosphate were observed in Huh7 cells and in primary hepatocytes in vitro. TMC647078 is a potent novel nucleoside inhibitor of HCV replication with a promising in vitro virology and biology profile.
authors.affiliation: Tibotec-Virco Virology BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Jan Martin
authors.initials: JM
authors.lastname: Berke
authors.forename: Leen
authors.initials: L
authors.lastname: Vijgen
authors.forename: Sophie
authors.initials: S
authors.lastname: Lachau-Durand
authors.forename: Megan H
authors.initials: MH
authors.lastname: Powdrill
authors.forename: Svea
authors.initials: S
authors.lastname: Rawe
authors.forename: Elena
authors.initials: E
authors.lastname: Sjuvarsson
authors.forename: Staffan
authors.initials: S
authors.lastname: Eriksson
authors.forename: Matthias
authors.initials: M
authors.lastname: Götte
authors.forename: Els
authors.initials: E
authors.lastname: Fransen
authors.forename: Pascale
authors.initials: P
authors.lastname: Dehertogh
authors.forename: Christel
authors.initials: C
authors.lastname: Van den Eynde
authors.forename: Laurent
authors.initials: L
authors.lastname: Leclercq
authors.forename: Tim H M
authors.initials: TH
authors.lastname: Jonckers
authors.forename: Pierre
authors.initials: P
authors.lastname: Raboisson
authors.forename: Magnus
authors.initials: M
authors.lastname: Nilsson
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Åsa
authors.initials: Å
authors.lastname: Rosenquist
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Fanning
authors.forename: Tse-I
authors.initials: TI
authors.lastname: Lin
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D003562:Cytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D010641:Phenotype; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D013141:Spiro Compounds / Q000378:metabolism / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D003562:Cytidine; D003842:Deoxycytidine Kinase; D011480:Protease Inhibitors; D012367:RNA, Viral; D013141:Spiro Compounds; D017361:Viral Nonstructural Proteins; C554513:2'-deoxy-2'-spirocyclopropylcytidine; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase