Anti-HIV and anti-HBV activity and resistance profile of 2',3'-dideoxy-3'-thiacytidine (3TC) and its arylphosphoramidate derivative CF 1109

Biochem Biophys Res Commun. 1996 Aug 14;225(2):363-9. doi: 10.1006/bbrc.1996.1181.

Abstract

A novel membrane-soluble prodrug of the 5'-monophosphate derivative of 3TC containing a phenyl group and the methyl ester of L-alanine linked to the phosphorus through a phosphoramidate bond with the primary amino moiety (designated Cf 1109) was prepared. The 3TC prodrug proved less potent an inhibitor of HIV-1 and HIV-2 replication in CEM cell cultures than 3TC, but lost only 20-fold antiviral potency in 2'-deoxycytidine kinase-deficient CEM/dCK- cells compared with a more than 2,000-fold decrease of activity of 3TC. In contrast, 3TC and Cf 1109 proved equally highly effective in inhibiting HBV release in supernatants of HBV-transfected Hep G2 2.2.15 cell cultures (50% effective concentration approximately 0.02 microM). Both compounds easily selected for highly resistant HIV-1 strains at a comparable speed of breakthrough. The mutant viruses contained an 184-Ile and/or 184-Val amino acid change in their reverse transcriptase. Our data are suggestive for a relatively poor delivery of 3TC-MP in the intact CEM cells but a remarkably high delivery of 3TC and/or 3TC-MP in the intact Hep G2 2.2.15 cells.

MeSH terms

  • Antiviral Agents / pharmacology*
  • Base Sequence
  • Cell Line
  • DNA Primers
  • Drug Resistance, Microbial / genetics
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • HIV-1 / physiology
  • Hepatitis B virus / drug effects*
  • Hepatitis B virus / physiology
  • Humans
  • Lamivudine
  • Molecular Sequence Data
  • Mutation
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Virus Replication / drug effects
  • Zalcitabine / analogs & derivatives*
  • Zalcitabine / chemistry
  • Zalcitabine / pharmacology

Substances

  • Antiviral Agents
  • DNA Primers
  • Reverse Transcriptase Inhibitors
  • Lamivudine
  • Zalcitabine