A nucleoside analogue of 2, 4-difluoropyridine has potential as an antiretroviral agent with multiple and unique mechanisms of action, and may be effective against the HIV organism.
The high rate of mutation which is inherent in reverse transcription of the HIV genome is a result of the lack of proof-reading function of the reverse transcriptase enzyme. This has allowed the HIV virus to develop resistance to multiple antiviral agents. It may be possible to use this viral property to advantage by treatment with an antiviral nucleoside analogue which is a close structural isostere of uridine and deoxyuridine. The drug is unable to form hydrogen bonds with adenine and will be excluded from host cell DNA by its 3' to 5' proof-reading exonuclease activity. However, reverse transcriptase, which has no such mechanism, will allow incorporation of the drug into proviral DNA. The drug will have an inhibitory effect on RNase H function. It will also be expected to cause delay in elongation at those sites in the template strand that contain two or more adjacent adenine bases, because two drug molecules will, for practical purposes, never be inserted in the same strand next to each other. The length of the delay in strand elongation will therefore be a function of the availability of the natural NTP or dNTP. Both the rate and fidelity of protein synthesis will be affected by the drug. There will be decreased stability of the proviral double stranded DNA and if the proviral DNA is able to integrate into the host cell chromosome, double stranded breaks may be produced by the host cells' DNA repair mechanisms. Finally there will be a specific 'strand trade' mutation that the drug will induce specifically into viral but not into cellular genetic material.
Peasley
K
K
Columbia, Kentucky, USA.
D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D016368:Frameshift Mutation; D015696:Gene Products, tat / Q000502:physiology; D006678:HIV / Q000187:drug effects / Q000235:genetics; D009705:Nucleosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016914:Ribonuclease H / Q000037:antagonists & inhibitors; D015534:Trans-Activators / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus
C420107:1,4-anhydro-(2,4-difluoropyridyl)pentitol; C420108:1,4-anhydro-2-deoxy-C-(2,4-difluoropyridyl)pentitol; D019380:Anti-HIV Agents; D015696:Gene Products, tat; D009705:Nucleosides; D011725:Pyridines; D015534:Trans-Activators; D054322:tat Gene Products, Human Immunodeficiency Virus; D016914:Ribonuclease H