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

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.
AuthorsVictor E Marquez, Stephen H Hughes, Shizuko Sei, Riad Agbaria
JournalAntiviral research (Antiviral Res) Vol. 71 Issue 2-3 Pg. 268-75 (Sep 2006) ISSN: 0166-3542 [Print] Netherlands
PMID16730077 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Review)
Chemical References
  • Antiviral Agents
  • Nucleosides
  • (north)-methanocarbathymidine
  • Thymidine
Topics
  • Animals
  • Antiviral Agents (chemistry, pharmacology)
  • Chlorocebus aethiops
  • Herpesvirus 1, Human (drug effects)
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Models, Chemical
  • Nucleosides (chemistry, pharmacology)
  • Simplexvirus (drug effects)
  • Thymidine (analogs & derivatives, chemistry, pharmacology)
  • Vero Cells

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