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.