Deoxythioguanosine triphosphate impairs HIV replication: a new mechanism for an old drug.
Inhibition of HIV-1 reverse transcriptase (RT) and HIV protease are effective mechanisms for anti-retroviral agents, and the combined use of mechanistically different medications has markedly improved the treatment of HIV infected patients. The active metabolite of mercaptopurine and thioguanine (TG), deoxythioguanosine triphosphate, was shown to be incorporated into DNA by the polymerase function of HIV-1 RT and then to abrogate RNA cleavage by HIV-1 RNaseH. Treatment of human lymphocyte cultures with thioguanine produced substantial inhibition of HIV replication (IC(50)=0.035 microM, IC(95)=15.4 microM), with minimal toxicity to host lymphocytes (<10% at 15.4 microM TG, P<0.000005). Furthermore, low concentrations of TG and zidovudine were synergistic in inhibiting HIV replication in human lymphocytes (synergy volume=19 microM(2)%), without additive cytotoxicity to host lymphocytes. Thus, thiopurines are novel anti-retroviral agents that alter the DNA-RNA substrates for HIV RNaseH, thereby abrogating early stages of HIV replication.
Krynetskaia
N F
NF
St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, TN 38105, USA.
Feng
J Y
JY
Krynetski
E Y
EY
Garcia
J V
JV
Panetta
J C
JC
Anderson
K S
KS
Evans
W E
WE
D019380:Anti-HIV Agents / Q000494:pharmacology*; D001483:Base Sequence; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D003848:Deoxyguanine Nucleotides / Q000378:metabolism*; D054303:HIV Reverse Transcriptase / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D015122:Mercaptopurine / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009692:Nucleic Acid Heteroduplexes; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D011108:Polymers; D012313:RNA / Q000378:metabolism; D016914:Ribonuclease H / Q000378:metabolism; D013866:Thioguanine / Q000494:pharmacology*; D013873:Thionucleotides / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D003848:Deoxyguanine Nucleotides; D009692:Nucleic Acid Heteroduplexes; D019384:Nucleic Acid Synthesis Inhibitors; D011108:Polymers; D013873:Thionucleotides; C021173:2'-deoxy-6-thioguanosine 5'-triphosphate; D012313:RNA; D004247:DNA; D015122:Mercaptopurine; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H; D013866:Thioguanine