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

Furman, Phillip A.; Wilson, Joan G.; Reardon, John E.; Painter, George R.

doi:10.1177/095632029500600601

Cited by 55 publications

(49 citation statements)

References 43 publications

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“…Emtricitabine is consistently (4-10 times) more patent than lamivudine (3TC) in vitro against laboratory strains and primary clinical isolates of HIV (Schinazi et al, 1992;Schinazi et al, 1993;Tisdale et al, 1993). As a nucleoside reverse transcriptase inhibitor (NRTI), emtricitabine is readily anabolized by cellular enzymes in a step wise fashion to form its mono phosphate, diphosphate, and finally 5΄-triphosphate (TP) form, the active intracellular moiety that inhibits HIV-1 reverse transcriptase (RT) and HBV DNA polymerase (Wilson et al, 1993;Furman et al, 1995;Davis et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

A Bioequivalence Study Comparing Two Formulation of Emtricitabine Capsules

Adla¹,

Syedba²

2010

JBB

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This investigation was carried out to evaluate the bioavailability of emtricitabine 200mg capsules (Test) of Aurobindo Pharma Ltd, India, relative to reference product, Emtriva 200mg capsules, manufactured by Gilead Sciences, Inc., USA. The bioavailability study was carried out on 36 healthy male volunteers who received a single dose of emtricitabine 200mg of the test (T) and the reference ( R ) products in the fasting state, in a randomized, balanced, 2-way cross-over design. After dosing, serial blood samples were collected for a period of 48 hours. Plasma obtained from blood was analyzed for emtricitabine by a sensitive and validated simultaneous liquid-chromatographic and mass-spectrometric (LC-MS/ MS) assay. The maximum plasma concentrations (C max ), area under the plasma concentration-time curve up to the last measurable concentration (AUC 0-t ), and to infinity (AUC 0-α ) and the time to maximum concentration (t max ) were analyzed statistically. The parametric confidence intervals (90%) were calculated. It was found that the test/ reference (T/R) ratios for the pharmacokinetic parameters (AUC 0-t ), (AUC 0-α ) and (C max ) were well within the Bioequivalence acceptance range of 80 -125% as per international regulatory guidelines. Therefore, the two formulations were considered to be bioequivalent.

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Section: Introductionmentioning

confidence: 99%

A Bioequivalence Study Comparing Two Formulation of Emtricitabine Capsules

Adla¹,

Syedba²

2010

JBB

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“…The recent demonstration of the stereoselectivity of HBV DNA polymerase (Schinazi et el., 1994;Furman et et., 1995) has provided the stimulation to synthesize the corresponding enantiomer as well as other~-L purine analogues. 3TC and its 5-fluoro derivative~-L-FTC are markedly more potent inhibitors than their o-enantiomer counterparts against both HIV (Coates et el., 1992;Schinazi et el., 1992) and HBV replication (Furman et el., 1992;Schinazi et el., 1992).…”

Section: Anti-hbv Activity Off3-l-dda and Derivatives 277mentioning

confidence: 99%

“…have demonstrated potent and highly selective anti-HIV and anti-HBV activities in vitro in several human cell lines and in vivo (Coates et a/., 1992;Furman et a/., 1992Furman et a/., , 1995Schinazi et ei., 1992;van Draanen et a/., 1994;Gosselin et a/., 1994a,b;Lin et el., 1994;Schinazi et sl., 1994;Mansour et el., 1995). On the basis of this finding, novel series of purine~-L-2',3'-dideoxynucleoside analogues were synthesized in order to evaluate their potential anti-HBV activity in the HBV DNA-transfected human hepatoblastoma-derived Hep-G2 cells (2.2.15 cells) and to study their potential structure-activity relationship.…”

mentioning

confidence: 99%

Inhibition of Hepatitis B Virus Replication by Nucleoside Enantiomers of β-2′,3′-Dideoxypurine Analogues

Alaoui

Faraj

Pierra

et al. 1996

Antivir Chem Chemother

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Various purine β-L-2′,3′-dideoxynucleoside analogues with both sugar and base modifications including β-L-ddG, β-L-ddl, β-L-ddA, 2′-azido-β-L-araddA, 2′-amino-β-L-araddA, 2′,5′-anhydro-β-L-araddA, 2′-azido-β-L-ddA, 2′-amino-β-L-ddA, 2′-fluoro-β-L-ddA, 3′-azido-β-L-ddA, 3′-amino-β-L-ddA, 3′-fluoro-β-L-ddA, 2,6-diamino-β-L-2′,3′-dideoxyfuranosylpurine, 6-cyclopropylamino-β-L-ddA, 2′-azido-6-N-triphenylphosphine-β-L-araddA, 2-amino-6-methylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2-amino-6-cyclopropylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2-amino-6-cyclopentylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2′,3′-didehydro-β-L-ddA and 2′,3′-didehydro-6-N-triphenyl phosphine-β-L-ddA were synthesized and evaluated as potential inhibitors of hepatitis B virus (HBV) replication in HBV DNA-transfected human hepatoblastoma-derived Hep-G2 cells (2.2.15 cells). β-L-ddA, 2′-azido-β-L-ddA, 3′-azido-β-L-ddA, 2″,3′-didehydro-β-L-ddA (β-L-D4A) and a modified base of β-L-D4A, inhibited HBV replication in vitro. β-L-D4A was the more potent and selective antiHBV agent with a 50% effective concentration value of 0.1 μM and a selectivity index of 1800. On the basis of this finding, studies are in progress to synthesize new purine derivatives with the β-L unnatural configuration which hopefully will lead to identifying additional potent and highly selective anti-HBV agents.

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“…LddA (β-L-2′,3′-dideoxyadenosine) also presents a fairly important anti-HBV activity in infected cell systems (Bolon et al, 1996). The enantiomers of the guanosine analogue carbovir (CBV) have different levels of activity, the natural β-D-enantiomer being active against HIV and the β-L-enantiomer against HBV (Furman et al, 1995).…”

Section: L-nucleoside Analogues With Antiviral (Anti-hiv or Anti-hbv)mentioning

confidence: 99%

“…Thus, cellular deoxycytidine kinase has a considerably relaxed enantioselectivity with respect to a large number of nucleosides or their analogues, and it occupies a strategic position in the intracellular activation of Introduction Hutchinson, 1990;Mahmoudian et al, 1993). Lately, however, the enantioselectivity of some of these enzymes has been questioned and recognized as an important factor for the recently disclosed antiviral activity of several L-nucleoside analogues, especially against human immunodeficiency virus (HIV) or hepatitis B virus (HBV) (Furman et al, 1995). It is now accepted that these activities may resultat least in part -from the relaxed enantioselectivities of the target viral enzymes or the cellular enzymes which activate or deactivate the nucleoside analogues.…”

mentioning

confidence: 99%

The Enantioselectivity of Enzymes Involved in Current Antiviral Therapy Using Nucleoside Analogues: A New Strategy?

Maury

2000

Antivir Chem Chemother

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This review is primarily intended for synthetic bio-organic chemists and enzymologists who are interested in new strategies in the design of virus inhibitors. It is an attempt to assess the importance of the enzymatic properties of L-nucleosides and their analogues, particularly those that are active against viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), herpes simplex virus (HSV), etc. Only data obtained with purified enzymes have been considered and discussed. The examined enzymes include nucleoside- or nucleotide-phosphorylating enzymes, catabolic enzymes, viral target enzymes and cellular polymerases. The enantioselectivities of these enzymes were determined from existing data and are significant only when a sufficient number of enantiomeric pairs of substrates could be examined. The reported data emphasize the weak enantioselectivities of cellular or viral nucleoside kinases and some viral DNA polymerases. Thus, cellular deoxycytidine kinase has a considerably relaxed enantioselectivity with respect to a large number of nucleosides or their analogues, and it occupies a strategic position in the intracellular activation of the compounds. Similarly, HIV-1 reverse transcriptase often has a relatively weak enantioselectivity and can be inhibited by the 5-triphosphates of a large series of L-nucleosides and analogues. In contrast, degradation enzymes, such as adenosine or cytidine deaminases, generally demonstrate strict enantioselectivities favouring D-enantiomers and are used by chemists in asymmetric syntheses. The weak enantioselectivities of some enzymes involved in nucleoside metabolism are more or less pronounced, and one enantiomer or the other is favoured depending on the substrate. This suggests that the low enantioselectivity is fortuitous and does not result from evolutionary pressure, since these enzymes do not create or modify asymmetric centres in substrates. The combined enantioselectivities of the enzymes examined in this review strongly suggest that the field of L-nucleosides and their analogues should be systematically explored in the search for new virus inhibitors.

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

Cited by 55 publications

References 43 publications

A Bioequivalence Study Comparing Two Formulation of Emtricitabine Capsules

A Bioequivalence Study Comparing Two Formulation of Emtricitabine Capsules

Inhibition of Hepatitis B Virus Replication by Nucleoside Enantiomers of β-2′,3′-Dideoxypurine Analogues

The Enantioselectivity of Enzymes Involved in Current Antiviral Therapy Using Nucleoside Analogues: A New Strategy?

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