Novel human immunodeficiency virus (HIV) inhibitors that have a dual mode of anti-HIV action.
We have found that novel pyridine oxide derivatives are inhibitors of a wide range of human immunodeficiency virus (HIV) type 1 (HIV-1) and HIV-2 strains in CEM cell cultures. Some of the compounds showed inhibitory activities against recombinant HIV-1 reverse transcriptase (RT), whereas others were totally inactive against this viral protein in vitro. Partial retention of anti-HIV-1 activity against virus strains that contain a variety of mutations characteristic of those for resistance to nonnucleoside RT inhibitors and a lack of inhibitory activity against recombinant HIV-2 RT suggested that these pyridine oxide derivatives possess a mode of antiviral action independent from HIV RT inhibition. Time-of-addition experiments revealed that these pyridine oxide derivatives interact at a postintegration step in the replication cycle of HIV. Furthermore, it was shown that these compounds are active not only in acutely HIV-1-infected cells but also in chronically HIV-infected cells. A dose-dependent inhibition of virus particle release and viral protein expression was observed upon exposure to the pyridine oxide derivatives. Finally, inhibition of HIV-1 long terminal repeat-mediated green fluorescence protein expression in quantitative transactivation bioassays indicated that the additional target of action of the pyridine oxide derivatives may be located at the level of HIV gene expression.
D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D049452:Green Fluorescent Proteins; D006678:HIV / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008826:Microbial Sensitivity Tests; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
D019380:Anti-HIV Agents; D008164:Luminescent Proteins; D011726:Pyridinium Compounds; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D014764:Viral Proteins; D049452:Green Fluorescent Proteins; D054303:HIV Reverse Transcriptase