RESUMEN
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.
Asunto(s)
Fármacos Anti-VIH , Azacitidina/análogos & derivados , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Mutación , Nucleósidos/farmacología , Animales , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/toxicidad , Azacitidina/química , Azacitidina/farmacología , Azacitidina/toxicidad , Línea Celular , Cricetinae , VIH-1/genética , VIH-1/crecimiento & desarrollo , Humanos , Pruebas de Sensibilidad Microbiana , Nucleósidos/química , Nucleósidos/uso terapéutico , Nucleósidos/toxicidad , Inhibidores de la Transcriptasa Inversa/farmacología , Zidovudina/farmacologíaRESUMEN
Decitabine is a DNA methyltransferase inhibitor under development by SuperGen Inc and MGI Pharma Inc for the potential treatment of a range of hematological malignancies, including myelodysplastic syndrome, solid tumors and sickle cell disease.