Effects of (-)-2'-deoxy-3'-thiacytidine (3TC) 5'-triphosphate on human immunodeficiency virus reverse transcriptase and mammalian DNA polymerases alpha, beta, and gamma

Abstract

36:733-739, 1992). The effect of 3TC 5'-triphosphate on both the RNA-dependent and DNA-dependent activities of human immunodeficiency virus type 1 reverse transcriptase and DNA polymerases alpha, beta, and gamma from HeLa cells was investigated. 3TC 5'-triphosphate is a competitive inhibitor (with respect to dCTP) of the RNA-dependent DNA polymerase activity (apparent Ki = 10.6 1.0 to 12.4 5.1 ,uM, depending on the template and primer used); the DNA-dependent DNA polymerase activity is 50%o inhibited by a 3TC 5'-triphosphate concentration of 23.4 + 2.5 ,uM when dCTP is present at a concentration equal to its Km value. Chain elongation studies show that 3TC 5'-triphosphate is incorporated into newly synthesized DNA and that transcription is terminated in a manner identical to that found for ddCTP. The 50%o inhibitory concentrations of 3TC 5'-triphosphate against DNA polymerases alpha, beta, and gamma at concentrations of dCTP equal to the Km were 175 31, 24.8 10.9, and 43.8 16.4 ,uM, respectively. More detailed kinetic studies with 3TC 5'-triphosphate and DNA polymerases beta and gamma are consistent with the fact that inhibition of these enzymes by 3TC 5'-triphosphate is competitive with respect to dCTP. The values of Ki were determined to be 18.7 ,uM for DNA polymerase beta and 15.8 0.8 ,uM for DNA polymerase gamma.

The Effect of Absolute Configuration on the Anti-HIV and Anti-HBV Activity of Nucleoside Analogues

“…These values are quite high and taken together with other biochemical data would help to explain the lack of cytotoxicity seen with 3TC. In contrast, the 5'-triphosphate of the 1-~-D enantiomer of 3TC had a Kj value of 0.049 ± 0.005 uM for the human DNA polymerase y (Hart et al, 1992). This lack of selectivity for the viral versus the host enzyme could explain the differences in toxicity seen between 3TC and its 1-~-D enantiomer.…”

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

“…[The following references were cited only in Table 1: Barile et al, 1994Barile et al, , 1997Benbrik et al, 1997;Browne et al, 1993;Chen and Cheng, 1992;Cherrington et al, 1995;Corcuera et al, 1996;Cui et al, 1997;Dalakas et al, 1990;Elimadi et al, 1997. The following references were cited only in Table 1: Feldman and Anderson, 1994;Feldman et al, 1992;Hart et al, 1992;Hertzberg et al, 1992;Hobbs et al, 1992Hobbs et al, , 1995; Institute of Medicine (US) Committee to Review the Fialuridine (FIAU/FIAC) Clinical Trials, 1995;Izuta et al, 1991. The following references were cited only in Table 1: Modica-Napolitano, 1993;Nusbaum and Joseph, 1996;Parker et al, 1991;Pereira et al, 1998;Richardson et al, 1994;Schroder et al, 1996;Stevenson et al, 1995;Tsai et al, 1994.…”

“…Mitochondrial structural changes and lipid accumulation in nerves of DDC-treated rabbits. Anderson et al, 1992Chen and Cheng, 1992Chen and Cheng, 1989Chen et al, 1991Cherrington et al, 1995Eriksson et al, 1995Feldman et al, 1992Feldman and Anderson, 1994Keilbaugh et al, 1993Kukhanova et al, 1995Martin et al, 1994Starnes and Cheng, 1987Tsai et al, 1994 3TC Kinetics with HeLa DNA pol-␥ Hart et al, 1992Martin et al, 1994 Carbovir K m with gapped duplex DNA Parker et al, 1991White et al, 1989 Continued…”

Résistance du VIH aux antirétroviraux

“…Il s'agit des inhibiteurs nucléosidiques de la transcriptase inverse (INTI), des inhibiteurs non-nucléosidiques de la transcriptase inverse (INNTI) et des inhibiteurs de la protéase (IP). Les INTI, qui entrent en compétition avec les nucléosides naturels, empêchent l'élongation de la chaîne d'ADN [6,7]. Les INNTI agissent comme antagonistes non compé-titifs en se liant à une région hydrophobe adjacente au site catalytique de la TI [8,9].…”