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Deoxythioguanosine triphosphate impairs HIV replication: a new mechanism for an old drug

NATALIA F. KRYNETSKAIA¹, JOY Y. FENG^*,1, EUGENE Y. KRYNETSKI, J. VICTOR GARCIA, JOHN C. PANETTA, KAREN S. ANDERSON^* and WILLIAM E. EVANS²

St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA;
^* Yale University School of Medicine, New Haven, Connecticut, USA; and
University of Texas, Southwestern Medical Center, Dallas, Texas, USA

²Correspondence: St. Jude Children’s Research Hospital, 332 N. Lauderdale St., Memphis, TN 38105, USA. E-mail: william.evans{at}stjude.org

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 (IC₅₀=0.035 µM, IC₉₅=15.4 µM), with minimal toxicity to host lymphocytes (<10% at 15.4 µM TG, P<0.000005). Furthermore, low concentrations of TG and zidovudine were synergistic in inhibiting HIV replication in human lymphocytes (synergy volume=19 µM² %), 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., Feng, J. Y., Krynetski, E. Y., Garcia, J. V., Panetta, J. C., Anderson, K. A., Evans, W. E. Deoxythioguanosine triphosphate impairs HIV replication: a new mechanism for an old drug.

Key Words: thiopurines • thioguanylated DNA • viral RNase H

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