1. KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis.
- Author
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Harris KS, Brabant W, Styrchak S, Gall A, and Daifuku R
- Subjects
- Animals, Azacitidine chemistry, Azacitidine pharmacology, Azacitidine toxicity, Cell Line, Cricetinae, HIV-1 genetics, HIV-1 growth & development, Humans, Microbial Sensitivity Tests, Nucleosides chemistry, Nucleosides therapeutic use, Nucleosides toxicity, Reverse Transcriptase Inhibitors pharmacology, Zidovudine pharmacology, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, Anti-HIV Agents toxicity, Azacitidine analogs & derivatives, HIV Infections drug therapy, HIV-1 drug effects, Mutation, Nucleosides pharmacology
- 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.
- Published
- 2005
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