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Molecular Pharmacology

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Research ArticleArticle

Reverse Transcriptase Activity of Hepatitis B Virus (HBV) DNA Polymerase within Core Capsid: Interaction with Deoxynucleoside Triphosphates and Anti-HBV l-Deoxynucleoside Analog Triphosphates

Wing Lam, Ying Li, Jieh-Yuan Liou, Ginger E. Dutschman and Yung-chi Cheng
Molecular Pharmacology February 2004, 65 (2) 400-406; DOI: https://doi.org/10.1124/mol.65.2.400
Wing Lam
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Ying Li
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Jieh-Yuan Liou
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Ginger E. Dutschman
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Yung-chi Cheng
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Abstract

The use of L(–)SddC [β-l-2′,3′-dideoxy-3′-thiacytidine (lamivudine, 3TC)] for the treatment of Herpes B virus (HBV) infection is hindered by the emergence of drug-resistance associated with the L526M, L550V, and L526M/M550V mutations of the viral DNA polymerase (DP). The interactions of the anti-HBV compounds 2′,3′-dideoxy-2′,3′-didehydro-β-l(–)-5-fluorode-oxycytidine and 2′-fluoro-5-methyl-β-l-arabinofuranosyluracil triphosphate with HBV DP and its L(–)SddC-associated mutants have not been studied. The e antigen-negative variant of HBV associated with the G1896A mutation in the precore region has a high prevalence. Its effect on HBV DP is unclear. Because HBV DNA synthesis occurs in the nucleocapsid, we examined the kinetics of the reverse transcriptase activity from wild-type (wt) and mutated DPs with the wt or G1896A-mutated RNA template in the nucleocapsid. The effects of this template mutation on the activities of these l-nucleoside triphosphates were also examined. Results indicated that these DP mutations increased the Km values of deoxy-NTPs and decreased the efficiencies (Vmax/Km) of DPs. The additional L526M mutation increased the efficiency of the M550V-mutated DP but no more than that of the L526M-mutated DP. The G1896A mutation had impacts on the interactions between different DPs and deoxy-NTPs, except dCTP. It also had different impacts on the actions of the l-nucleoside triphosphates toward DPs. The L526M and M550V mutations caused a greater decrease in the Vmax using the wt RNA template compared with the G1896A-mutated template. The L526M, M550V, and L526M/M550V mutations caused varying degrees of resistance to the different l-nucleoside triphosphates.

  • Received June 17, 2003.
  • Accepted October 30, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 65 (2)
Molecular Pharmacology
Vol. 65, Issue 2
1 Feb 2004
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Research ArticleArticle

Reverse Transcriptase Activity of Hepatitis B Virus (HBV) DNA Polymerase within Core Capsid: Interaction with Deoxynucleoside Triphosphates and Anti-HBV l-Deoxynucleoside Analog Triphosphates

Wing Lam, Ying Li, Jieh-Yuan Liou, Ginger E. Dutschman and Yung-chi Cheng
Molecular Pharmacology February 1, 2004, 65 (2) 400-406; DOI: https://doi.org/10.1124/mol.65.2.400

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Research ArticleArticle

Reverse Transcriptase Activity of Hepatitis B Virus (HBV) DNA Polymerase within Core Capsid: Interaction with Deoxynucleoside Triphosphates and Anti-HBV l-Deoxynucleoside Analog Triphosphates

Wing Lam, Ying Li, Jieh-Yuan Liou, Ginger E. Dutschman and Yung-chi Cheng
Molecular Pharmacology February 1, 2004, 65 (2) 400-406; DOI: https://doi.org/10.1124/mol.65.2.400
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