title: Antiviral activity of Bay 41-4109 on hepatitis B virus in humanized Alb-uPA/SCID mice.
abstract: Current treatments for HBV chronic carriers using interferon alpha or nucleoside analogues are not effective in all patients and may induce the emergence of HBV resistant strains. Bay 41-4109, a member of the heteroaryldihydropyrimidine family, inhibits HBV replication by destabilizing capsid assembly. The aim of this study was to determine the antiviral effect of Bay 41-4109 in a mouse model with humanized liver and the spread of active HBV. Antiviral assays of Bay 41-4109 on HepG2.2.15 cells constitutively expressing HBV, displayed an IC(50) of about 202 nM with no cell toxicity. Alb-uPA/SCID mice were transplanted with human hepatocytes and infected with HBV. Ten days post-infection, the mice were treated with Bay 41-4109 for five days. During the 30 days of follow-up, the HBV load was evaluated by quantitative PCR. At the end of treatment, decreased HBV viremia of about 1 log(10) copies/ml was observed. By contrast, increased HBV viremia of about 0.5 log(10) copies/ml was measured in the control group. Five days after the end of treatment, a rebound of HBV viremia occurred in the treated group. Furthermore, 15 days after treatment discontinuation, a similar expression of the viral capsid was evidenced in liver biopsies. Our findings demonstrate that Bay 41-4109 displayed antiviral properties against HBV in humanized Alb-uPA/SCID mice and confirm the usefulness of Alb-uPA/SCID mice for the evaluation of pharmaceutical compounds. The administration of Bay 41-4109 may constitute a new strategy for the treatment of patients in escape from standard antiviral therapy.
authors.affiliation: INSERM, National Institute of Health and Medical Research, Unit 845, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Brezillon
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Brunelle
authors.forename: Hélène
authors.initials: H
authors.lastname: Massinet
authors.forename: Eric
authors.initials: E
authors.lastname: Giang
authors.forename: Céline
authors.initials: C
authors.lastname: Lamant
authors.forename: Lucie
authors.initials: L
authors.lastname: DaSilva
authors.forename: Sophie
authors.initials: S
authors.lastname: Berissi
authors.forename: Jacques
authors.initials: J
authors.lastname: Belghiti
authors.forename: Laurent
authors.initials: L
authors.lastname: Hannoun
authors.forename: Gherard
authors.initials: G
authors.lastname: Puerstinger
authors.forename: Eva
authors.initials: E
authors.lastname: Wimmer
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Olivier
authors.initials: O
authors.lastname: Hantz
authors.forename: Patrick
authors.initials: P
authors.lastname: Soussan
authors.forename: Serban
authors.initials: S
authors.lastname: Morosan
authors.forename: Dina
authors.initials: D
authors.lastname: Kremsdorf
mesh_terms: D000418:Albumins / Q000378:metabolism*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001706:Biopsy / Q000379:methods; D004279:DNA, Viral / Q000378:metabolism; D006509:Hepatitis B / Q000188:drug therapy*; D006515:Hepatitis B virus / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007700:Kinetics; D008099:Liver / Q000378:metabolism / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D019562:Viral Load
chemical_list: D000418:Albumins; D000998:Antiviral Agents; C464059:BAY 41-4109; D004279:DNA, Viral; D011725:Pyridines; D011743:Pyrimidines