Effects of β-l-3′-azido-3′-deoxythymidine 5′-triphosphate on host and viral DNA polymerases

Faraj, Abdesslem; Alaoui, A.M. El; Gosselin, Gilles; Imbach, Jean‐Louis; Morrow, Casey D.; Sommadossi, Jean‐Pierre

doi:10.1016/s0166-3542(00)00095-4

Cited by 9 publications

(7 citation statements)

References 12 publications

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“…The K app m value obtained for dTTP for HIV-1 RT (9.05 ± 0.46 M) was similar to the values determined by others with the use of poly(rA)·p(dT) 12-18 (Matthes et al, 1989;Reardon and Miller, 1990), whereas K app m values for the substrate obtained for the studied recombinant human DNA polymerases ␥ and ␤ (2.61 ± 0.19 M and 78 ± 14 M, respec- tively) were significantly higher than those reported for the native polymerases isolated from mammalian cells and assayed with the use of the same template-primers as in the present study (Faraj et al, 2000;Hart et al, 1992;Martin et al, 1994). However, the observed difference between the K app m values for dTTP for both polymerases studied was similar to that demonstrated by others, and the low K app m for pol ␥ was diagnostic for this polymerase (Hart et al, 1992;Martin et al, 1994).…”

Section: Kinetics Of Incorporation Of Dtmpcontrasting

confidence: 50%

“…However, Matthes et al demonstrated poor sensitivity of polymerase ␣ for both 4-SFLTTP and FLTTP with IC 50 values of 140 M and above 200 M, respectively (Matthes et al, 1987(Matthes et al, , 1989. Additionally, many other inhibition studies showed that polymerase ␣ was less sensitive to other thymidine nucleotide analogues than polymerase ␥ and mostly similarly or even less sensitive to such compounds than polymerase ␤ (Faraj et al, 2000;Hart et al, 1992;Martin et al, 1994;Matthes et al, 1987). Moreover, it was demonstrated, that both polymerase and polymerase ␦ with IC 50 values for FLTTP over 100 M and 200 M, respectively (von Janta-Lipinski et al, 1998), likewise polymerase ␣, were mainly less sensitive to thymidine nucleotide analogues than both polymerases ␥ and ␤ (Focher et al, 1995;Huang et al, 1992;Martin et al, 1994;Yang et al, 2007).…”

Section: Inhibition Of Enzymes Versus In Vitro Anti-hiv-1 Activity Ofmentioning

confidence: 99%

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Partial selective inhibition of HIV-1 reverse transcriptase and human DNA polymerases γ and β by thiated 3′-fluorothymidine analogue 5′-triphosphates

et al. 2010

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a b s t r a c t 3 -Deoxy-3 -fluorothymidine (FLT, alovudine ® ) belongs to the most potent agents inhibiting HIV-1 replication. Its 5 -triphosphate (FLTTP) is a potent inhibitor of HIV-1 reverse transcriptase (HIV RT). Unfortunately, FLT exerts substantial hematologic toxicity both in vitro and in vivo. It was suggested that this toxicity may be related to inhibition of human DNA polymerases, especially mitochondrial DNA polymerase ␥, by nucleoside analogue 5 -triphosphates leading to termination of DNA synthesis and mitochondrial dysfunction. To decrease the toxicity of FLT, its thiated analogues, 4-SFLT and 2-SFLT, were previously synthesized and shown to be potent inhibitors of HIV-1 with low in vitro cytotoxicity. To explain this phenomenon in the present study the synthesis of 5 -triphosphates of thiated FLT analogues was undertaken and their interaction with recombinant HIV-1 RT and human DNA polymerases ␥ (pol ␥) and ␤ (pol ␤) was investigated. It was shown that 3 -deoxy-3 -fluoro-4-thiothymidine 5 -triphosphate (4-SFLTTP) and 3 -deoxy-3 -fluoro-2-thiothymidine 5 -triphosphate (2-SFLTTP) were, similarly to FLTTP, potent competitive inhibitors of HIV-1 RT, with K Of special interest is that 2-SFLTTP, showing syn conformation, is a less potent inhibitor of human mitochondrial pol ␥ than 4-SFLTTP and FLTTP, both in the anti conformation, and has a higher inhibitory activity against HIV-1 RT than 4-SFLTTP. Moreover, the parent nucleoside 2-SFLT possessing the syn conformation shows a more potent anti-HIV-1 activity and a better selectivity index than its 4-thio isomer in the anti conformation (Matthes et al., 1989;Poopeiko et al., 1995), 2-SFLT is a potent and selective anti-HIV-1 agent with the selectivity index 4-fold higher than that of FLT.Findings regarding the mechanisms of antiviral and cytotoxic activities of FLT and its thioanalogues are discussed.

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Section: Kinetics Of Incorporation Of Dtmpcontrasting

confidence: 50%

Section: Inhibition Of Enzymes Versus In Vitro Anti-hiv-1 Activity Ofmentioning

confidence: 99%

Partial selective inhibition of HIV-1 reverse transcriptase and human DNA polymerases γ and β by thiated 3′-fluorothymidine analogue 5′-triphosphates

et al. 2010

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“…It is phosphorylated intracellularly to AZT-triphosphate (AZT-TP) by thymidine kinase, and is finally incorporated into viral DNA blocking chain elongation by RT (Falchetti et al, 2005). AZT-TP can also be incorporated into eukaryotic DNA in place of thymidine, although it has low affinity for DNA polymerases α, β, and γ and high affinity for RT (Faraj et al, 2000). The identification of the hTERT component of telomerase as a functional catalytic RT, structurally similar to HIV RT, prompted studies about the feasibility of inhibiting telomerase with known RT viral inhibitors, such as AZT (Hájec et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

AZT as a telomerase inhibitor

Gomez¹,

Armando²,

Alonso³

2012

Front. Oncol.

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Telomerase is a highly specialized reverse transcriptase (RT) and the maintenance of telomeric length is determined by this specific enzyme. The human holoenzyme telomerase is a ribonucleoprotein composed by a catalytic subunit, hTERT, an RNA component, hTR, and a group of associated proteins. Telomerase is normally expressed in embryonic cells and is repressed during adulthood. The enzyme is reexpressed in around 85% of solid tumors. This observation makes it a potential target for developing drugs that could be developed for therapeutic purposes. The identification of the hTERT as a functional catalytic RT prompted studies of inhibiting telomerase with the HIV RT inhibitor azidothymidine (AZT). Previously, we have demonstrated that AZT binds preferentially to telomeres, inhibits telomerase and enhances tumor cell senescence, and apoptosis after AZT treatment in breast mammary adenocarcinoma cells. Since then, several studies have considered AZT for telomerase inhibition and have led to potential clinical strategies for anticancer therapy. This review covers present thinking of the inhibition of telomerase by AZT and future treatment protocols using the drug.

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“…Ab initio theoretical calculations are proving to be useful tools for investigating a wide range of important biologic complexes 1, 2. Nucleoside analogs 3–52 constitute a family of biologic molecules that play an important role in the transcription process of the human immunodeficiency syndrome (HIV) virus. This class includes AZT (Fig.…”

Section: Introductionmentioning

confidence: 99%

Investigation of nucleoside analogs with anti‐HIV activity

Arissawa

Taft

Felcman

2003

Int J of Quantum Chemistry

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ABSTRACT:Although a relatively large number of drugs that inhibit human immunodeficiency syndrome (HIV)-1 reverse transcriptase have been developed-such as AZT, d4T, ddI, 3TC, and ddC, which are chain terminating nucleoside analogs-resistance is still a major problem. Atomic charges, regioselective patterns of chemical reactivity, and other indices of biochemical activity may help us acquire a better understanding of how the drugs work and the mechanism of drug resistance. In this work, we investigated the above-mentioned nucleoside analogs using the ab initio Hartree-Fock method with 3-21G, 3-21G*, 6-31G, 6-31G*, 6-31G**, and 6-31ϩG** basis sets as well as B3LYP/6-31G**, including thus diffusion, polarization, and correlation effects to obtain fully optimized geometric parameters. Vibrational frequencies were calculated and we also investigated the effects of solvents, Mulliken, and natural bond orbital charge distribution, as well as hydrogen bond effects. We tried to correlate very low and very high anti-HIV activity with charges, vibrational stretching frequencies, interatomic distances, and the effect of solvents.

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Effects of β-l-3′-azido-3′-deoxythymidine 5′-triphosphate on host and viral DNA polymerases

Cited by 9 publications

References 12 publications

Partial selective inhibition of HIV-1 reverse transcriptase and human DNA polymerases γ and β by thiated 3′-fluorothymidine analogue 5′-triphosphates

Partial selective inhibition of HIV-1 reverse transcriptase and human DNA polymerases γ and β by thiated 3′-fluorothymidine analogue 5′-triphosphates

AZT as a telomerase inhibitor

Investigation of nucleoside analogs with anti‐HIV activity

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