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Deoxythioguanosine triphosphate impairs HIV replication: a new mechanism for an old drug
Author(s) -
KRYNETSKAIA NATALIA F.,
FENG JOY Y.,
KRYNETSKI EUGENE Y.,
GARCIA J. VICTOR,
PANETTA JOHN C.,
ANDERSON KAREN S.,
EVANS WILLIAM E.
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.01-0124com
Subject(s) - reverse transcriptase , zidovudine , rnase h , viral replication , protease , cytotoxicity , biology , virology , polymerase , rna , chemistry , dna , human immunodeficiency virus (hiv) , enzyme , virus , biochemistry , in vitro , gene , viral disease
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 μM, IC 95 =15.4 μM), with minimal toxicity to host lymphocytes (< 10% at 15.4 μM TG, P < 0.5). Furthermore, low concentrations of TG and zidovudine were synergistic in inhibiting HIV replication in human lymphocytes (synergy volume = 19 μM 2 %), without additive cytotoxicity to host lympho‐cytes. Thus, thiopurines are novel anti‐retroviral agents that alter the DNA‐RNA substrates for HIV RNaseH, thereby abrogating early stages of HIV replication.