title: Deoxycytidine deaminase-resistant stereoisomer is the active form of (+/-)-2',3'-dideoxy-3'-thiacytidine in the inhibition of hepatitis B virus replication.
abstract: 2',3'-Dideoxy-3'-thiacytidine (+/-)-SddC) was found to have potent activity against human hepatitis B virus as well as human immunodeficiency viruses in culture. The (-)form ((-)-SddC) which is resistant to deoxycytidine deaminase was found to be the more active antiviral stereoisomer than the (+)-form ((+)-SddC). The (+)-SddC is susceptible to deamination by deoxycytidine deaminase and is 25- and 12-fold more toxic than (-)-SddC in CEM cells in terms of anti-cell growth and anti-mitochondrial DNA synthesis, respectively. Similar results were obtained using a mixture of their 5-fluoro analogs ((+/-)-FSddC). Unlike 2',3'-dideoxycytidine, which is a potent inhibitor of mitochondrial DNA synthesis and results in such delayed toxicity as peripheral neuropathy with long term usage, (-)-SddC does not affect mitochondrial DNA synthesis. The (-)form is phosphorylated to (-)-SddCMP and is subsequently converted to (-)-SddCDP and (-)-SddCTP. One additional major metabolite which has been tentatively assigned the name "(-)-SddCMP sialate" was also identified. No significant difference in terms of the profiles of the metabolites was found between 4 and 24 h. There is an appreciable amount of (-)-SddCTP detectable 24 h after removal of the drug. (-)-SddCTP was also found to be approximately 3-fold more potent than (+)-SddCTP in inhibiting human hepatitis B virus DNA polymerase. This is the first nucleoside analog with the unnatural sugar configuration demonstrated to have antiviral activity.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
authors.forename: C N
authors.initials: CN
authors.lastname: Chang
authors.forename: S L
authors.initials: SL
authors.lastname: Doong
authors.forename: J H
authors.initials: JH
authors.lastname: Zhou
authors.forename: J W
authors.initials: JW
authors.lastname: Beach
authors.forename: L S
authors.initials: LS
authors.lastname: Jeong
authors.forename: C K
authors.initials: CK
authors.lastname: Chu
authors.forename: C H
authors.initials: CH
authors.lastname: Tsai
authors.forename: Y C
authors.initials: YC
authors.lastname: Cheng
authors.forename: D
authors.initials: D
authors.lastname: Liotta
authors.forename: R
authors.initials: R
authors.lastname: Schinazi
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003564:Cytidine Deaminase; D004261:DNA Replication / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000096:biosynthesis; D006515:Hepatitis B virus / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D019259:Lamivudine; D009700:Nucleoside Deaminases / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014162:Transfection; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D004272:DNA, Mitochondrial; D019259:Lamivudine; D016047:Zalcitabine; D009700:Nucleoside Deaminases; D003564:Cytidine Deaminase; C011530:deoxycytidine deaminase