title: KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis.
abstract: We report the activities of a novel nucleoside analog against HIV. This nucleoside (KP-1212) is not a chain terminator but exerts its antiviral effects via mutagenesis of the viral genome. Serial passaging of HIV in the presence of KP-1212 causes an increase in the mutation rate of the virus leading to viral ablation. HIV strains resistant to KP-1212 have not yet been isolated. Quite to the contrary, virus treated with KP-1212 exhibited an increased sensitivity not only to KP-1212 but also to another nucleoside reverse transcriptase inhibitor (NRTI), zidovudine. HIV strains resistant to other NRTIs (e.g. zidovudine, lamivudine, stavudine, abacavir, etc.) exhibited no cross-resistance towards KP-1212. Multiple assays confirmed that KP-1212 has a favorable (low) genotoxicity profile when compared to some approved antiviral nucleosides. In addition, KP-1212 is not toxic to mitochondria nor does it exhibit any inhibitory effects on mitochondrial DNA synthesis.
authors.affiliation: Koronis Pharmaceuticals Inc., 12277 134th Ct. N.E. Redmond, WA 98052, USA. kharris@koronispharma.com
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Harris
authors.forename: William
authors.initials: W
authors.lastname: Brabant
authors.forename: Sheila
authors.initials: S
authors.lastname: Styrchak
authors.forename: Alexander
authors.initials: A
authors.lastname: Gall
authors.forename: Richard
authors.initials: R
authors.lastname: Daifuku
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D006224:Cricetinae; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; C522536:KP 1461; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; C013938:5,6-dihydro-5-azacytidine; D015215:Zidovudine; D001374:Azacitidine