title: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, National Cancer Institute at Frederick, P.O. Box B, Building 539, Frederick, MD 21702, USA. marquezv@dc37a.nci.nih.gov
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
authors.forename: Shizuko
authors.initials: S
authors.lastname: Sei
authors.forename: Riad
authors.initials: R
authors.lastname: Agbaria
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology; D018139:Simplexvirus / Q000187:drug effects*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014709:Vero Cells
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; C469995:(north)-methanocarbathymidine; D013936:Thymidine