title: 3'-Deoxy phosphoramidate dinucleosides as improved inhibitors of hepatitis C virus subgenomic replicon and NS5B polymerase activity.
abstract: Phosphoramidate dinucleosides named "GC 3'-OH" series, carrying various phosphoramidate linkages have been previously reported as hepatitis C virus (HCV) inhibitors. To enhance the efficacy of these dinucleotides, we synthesized a novel "GC 3'-H" series as potential chain terminators. We showed that their inhibition potency is strongly increased by the introduction of novel neutral and bis-negatively charged phosphoramidate side chains. Their inhibitory effect on HCV NS5B polymerase was evaluated in vitro and in HCV subgenomic replicon containing Huh-6 cells. As expected, 3'-H compounds are more potent than their 3'-OH counterparts to inhibit HCV polymerase activity. The most potent inhibitor, a 5'-phosphorylated dinucleotide bearing a bis-negatively charged amino side chain (7), exhibits an IC(50) value of 8 μM in vitro and EC(50) value of 2.6 μM in the HCV subgenomic replicon system. A molecular structure model is presented to propose an interpretation of the gain afforded by the of 3'-H-cytidine modification.
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier 1-Université Montpellier 2, Place Eugène Bataillon, CC1704, 34095 Montpellier Cedex 5, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Priet
authors.forename: Ivan
authors.initials: I
authors.lastname: Zlatev
authors.forename: Ivan
authors.initials: I
authors.lastname: Barvik
authors.forename: Katrien
authors.initials: K
authors.lastname: Geerts
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Helene
authors.initials: H
authors.lastname: Dutartre
authors.forename: Bruno
authors.initials: B
authors.lastname: Canard
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Vasseur
authors.forename: François
authors.initials: F
authors.lastname: Morvan
authors.forename: Karine
authors.initials: K
authors.lastname: Alvarez
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors*; D016679:Genome, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D056004:Molecular Dynamics Simulation; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012367:RNA, Viral / Q000096:biosynthesis; D012093:Replicon / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D012321:DNA-Directed RNA Polymerases; D009705:Nucleosides; D009943:Organophosphorus Compounds; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase