The history of N-methanocarbathymidine: The investigation of a conformational concept leads to the discovery of a potent and selective nucleoside antiviral agent

Victor E. Marquez, Stephen H. Hughes, Shizuko Sei, Riad Agbaria

Research output: Contribution to journalShort surveypeer-review

52 Scopus citations

Abstract

Conformationally locked (North)-methanocarbathymidine (N-MCT) and (South)-methanocarbathymidine (S-MCT) have been used to investigate the conformational preferences of kinases and polymerases. The herpes kinases show a distinct bias for S-MCT, while DNA polymerases almost exclusively incorporate the North 5′-triphosphate (N-MCT-TP). Only N-MCT demonstrated potent antiviral activity against herpes simplex viruses (HSV-1 and 2) and Kaposi's sarcoma-associated herpesvirus (KSHV). The activity of N-MCT depends on its metabolic transformation to N-MCT-TP by the herpes kinases (HSV-tk or KSHV-tk), which catalyze the mono and diphosphorylation steps; cellular kinases generate the triphosphate. N-MCT at a dose of 5.6 mg/kg was totally protective for mice inoculated intranasally with HSV-1. Tumor cells that are not responsive to antiviral therapy became sensitive to N-MCT if the cells expressed HSV-tk. N-MCT given twice daily (100 mg/kg) for 7 days completely inhibited the growth of MC38 tumors derived from cells that express HSV-tk in mice while exhibiting no effect on tumors derived from non-transduced cells. After i.p. administration, N-MCT was rapidly absorbed and distributed in all organs examined with slow penetration into brain and testes. N-MCT-TP was also a potent inhibitor of HIV replication in human osteosarcoma (HOS) cells expressing HSV-tk.

Original languageEnglish
Pages (from-to)268-275
Number of pages8
JournalAntiviral Research
Volume71
Issue number2-3 SPEC. ISS.
DOIs
StatePublished - 1 Sep 2006

Keywords

  • DNA polymerases
  • Delayed chain termination
  • HIV reverse transcriptase
  • Herpes simplex virus
  • Kaposi's sarcoma-associated herpesvirus
  • Kinases

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