title: Inhibition of replication of hepatitis B virus by cytallene in vitro.
abstract: The acyclic cytosine nucleoside analog cytallene [1-(4'-hydroxy-1',2'-butadienyl)cytosine], which has both (+)- and (-)-enantiomers, was evaluated for its anti-hepatitis B virus (HBV) activity in 2.2.15 cells and was found to have potent activity against HBV DNA synthesis. The R-(-)-enantiomer was found to be the more active of the cytallene enantiomers, with a 50% inhibition concentration against HBV synthesis (HBIC50) of 0.08 microM. Its antiviral activity could be reversed by deoxycytidine (dC) and less efficiently by cytidine. Upon removal of the R-(-)-enantiomer from culture medium, the synthesis of HBV DNA could reinitiate, which suggested that the antiviral action is reversible. The R-(-)-enantiomer was also found to be more cytotoxic than the S-(+)-enantiomer. The degree of cytotoxicity varied among the cell lines, with a 50% inhibition of cell growth at greater than 10 microM. The R-(-)-enantiomer had no effect on HBV RNA synthesis and mitochondrial DNA synthesis at a concentration of 10 times or more than the HBIC50. The two enantiomers cannot be deaminated by dC deaminase, and they can be phosphorylated by cytoplasmic dC kinase. The R-(-)-enantiomer of cytallene is the first acyclic cytosine analog with potent inhibitory activity against HBV similar to those of other L-(-)-ddC analogs.
authors.affiliation: Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Y L
authors.initials: YL
authors.lastname: Zhu
authors.forename: S B
authors.initials: SB
authors.lastname: Pai
authors.forename: S H
authors.initials: SH
authors.lastname: Liu
authors.forename: K L
authors.initials: KL
authors.lastname: Grove
authors.forename: B C
authors.initials: BC
authors.lastname: Jones
authors.forename: C
authors.initials: C
authors.lastname: Simons
authors.forename: J
authors.initials: J
authors.lastname: Zemlicka
authors.forename: Y C
authors.initials: YC
authors.lastname: Cheng
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000187:drug effects; D004279:DNA, Viral / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D006514:Hepatitis B Surface Antigens / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D010766:Phosphorylation; D012367:RNA, Viral / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D004272:DNA, Mitochondrial; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D012367:RNA, Viral; C056908:cytallene; D003596:Cytosine