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Molecular Pharmacology

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Research ArticleArticle

Interaction of β-l-2′,3′-dideoxy-2′,3′-didehydro-5-fluoro-CTP with Human Immunodeficiency Virus-1 Reverse Transcriptase and Human DNA Polymerases: Implications for Human Immunodeficiency Virus Drug Design

Marina Kukhanova, Xiuyan Li, Shu-Hui Chen, Ivan King, Terrence Doyle, William Prusoff and Yung-Chi Cheng
Molecular Pharmacology May 1998, 53 (5) 801-807;
Marina Kukhanova
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Xiuyan Li
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Shu-Hui Chen
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Ivan King
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Terrence Doyle
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William Prusoff
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Yung-Chi Cheng
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Abstract

The work reported in this article has evaluated the relative molecular activity of the 5′-triphosphate of a novel β-l-nucleoside with an unsaturated ribose residue, β-l-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine (β-l-Fd4CTP), with that of β-l-2′,3′-dideoxy-5-fluorocytidine (β-l-FddCTP) and 2′,3′-dideoxycytidine (ddCTP), on DNA strand elongation by human immunodeficiency virus-1 reverse transcriptase (HIV RT) and human DNA polymerases α (pol α), β (pol β), γ (pol γ), and ε (pol ε). The concentrations of β-l-Fd4CTP that inhibited the yield of products by 50% were 0.20 μm, 1.8 μm, and 4.0 μm for HIV RT, pol γ, and pol β, respectively. The β-l-Fd4CTP at a concentration as high as 40 μm had no inhibitory effect on pol ε, but could inhibit pol α by 10–20% at 20 μm. TheKm and relativeVmax values of β-l-Fd4CTP, β-l-FddCTP, and ddCTP for incorporation into the standing start point of 5′-[32P]-oligonucleotide primer annealed with M13mp19 phage DNA by HIV RT and human DNA polymerases were evaluated. The efficiency of incorporation (Vmax/Km) of β-l-Fd4CTP by HIV RT was about 4-fold and 12-fold higher than that of ddCTP and β-l-FddCTP, respectively. In contrast, theVmax/Kmratio of β-l-Fd4CTP for pol γ was 7-fold lower than that of ddCTP, but 4-fold higher than that of β-l-FddCTP. Pol α could use β-l-Fd4CTP as a substrate, but only at a high concentration (>20 μm). Incorporation of β-l-Fd4CTP by pol ε could not be detected. A hypothesis about the preferable recognition of the 2′,3′-dideoxy-2′,3′-didehydro- structure of β-l-Fd4CTP to that of the 2′,3′-dideoxy-structure of β-l-FddCTP by HIV RT is discussed.

Footnotes

  • Send reprint requests to: Dr. Yung-Chi Cheng, Pharmacology Department, Yale University School of Med., 333 Cedar Street., New Haven, CT 06510.

  • This work was supported by National Institutes of Health Grant AI38204.

  • Abbreviations:
    HIV
    human immunodeficiency virus type 1
    HBV
    human hepatitis B virus
    pol
    polymerase
    RT
    reverse transcriptase
    dNTP
    2′-deoxynucleoside 5′-triphosphate
    dCTP
    2′-deoxycytidine 5′-triphosphate
    ddNTP
    2′,3′-dideoxynucleoside 5′-triposhate
    ddC
    2′,3′-dideoxycytidine
    ddCTP
    5′-triphosphate of ddC
    FddC
    5′-fluoro-analog of ddC
    FddCTP
    5′-triposphate of FddC
    Fd4C
    2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine
    Fd4CTP
    5′-triphosphate of FddC
    3TC
    β-l-2′,3′-dideoxy-3′-thiocytidine
    • Received December 2, 1997.
    • Accepted January 26, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 53 (5)
Molecular Pharmacology
Vol. 53, Issue 5
1 May 1998
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Research ArticleArticle

Interaction of β-l-2′,3′-dideoxy-2′,3′-didehydro-5-fluoro-CTP with Human Immunodeficiency Virus-1 Reverse Transcriptase and Human DNA Polymerases: Implications for Human Immunodeficiency Virus Drug Design

Marina Kukhanova, Xiuyan Li, Shu-Hui Chen, Ivan King, Terrence Doyle, William Prusoff and Yung-Chi Cheng
Molecular Pharmacology May 1, 1998, 53 (5) 801-807;

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Research ArticleArticle

Interaction of β-l-2′,3′-dideoxy-2′,3′-didehydro-5-fluoro-CTP with Human Immunodeficiency Virus-1 Reverse Transcriptase and Human DNA Polymerases: Implications for Human Immunodeficiency Virus Drug Design

Marina Kukhanova, Xiuyan Li, Shu-Hui Chen, Ivan King, Terrence Doyle, William Prusoff and Yung-Chi Cheng
Molecular Pharmacology May 1, 1998, 53 (5) 801-807;
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