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Chapter 8 : Hepatitis C Virus Polymerase as a Target for Antiviral Drug Intervention: Non-Nucleoside Inhibitors

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Abstract:

This chapter focuses on Hepatitis C virus (HCV) polymerase as a drug target for designing non-nucleoside inhibitors, and discusses details related to HCV sequence variation and quasispecies, HCV polymerase structure and mechanism, classes of polymerase inhibitors, inhibitors currently under development, the nature of drug resistance, and the need for combination therapy. Among the non-nucleoside inhibitors, compounds with thiophene carboxylic acid, pyranoindole, dihydropyranone, or phenylalanine scaffolds have been shown to bind to HCV polymerase in the thumb allosteric pocket by X-ray cocrystallization structures. C316Y and G554D appear to be the most important resistance mutations, suggesting overlapping resistance with HCV-796 and likely binding to the HCV polymerase active-site priming nucleotide pocket. Both sequence variations between genotypes and the quasispecies nature of HCV may contribute to drug resistance. Patients may have low levels of preexisting variants in their quasispecies that are resistant to antiviral drugs. These preexisting variants may be selected upon drug treatment and quickly become the dominant species. Many groups have reported on resistant mutants selected with various HCV polymerase inhibitors in vitro using the HCV replicon system. GSK reported several mutants against a benzothiadiazine (Compound 4), including M414T and N411S. Due to the high replication rate of HCV and errorprone nature of HCV polymerase, monotherapy will lead to the selection of preexisting resistance mutations and ultimately to the inability to eradicate HCV.

Citation: Liu Y, He Y, Molla A. 2009. Hepatitis C Virus Polymerase as a Target for Antiviral Drug Intervention: Non-Nucleoside Inhibitors, p 137-151. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch8

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Figures

Image of Figure 1.
Figure 1.

Polymerase-catalyzed nucleotidyl transfer reaction via the “two-metal-ion” mechanism.

Citation: Liu Y, He Y, Molla A. 2009. Hepatitis C Virus Polymerase as a Target for Antiviral Drug Intervention: Non-Nucleoside Inhibitors, p 137-151. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch8
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Image of Figure 2.
Figure 2.

Structures of non-nucleoside inhibitors binding to the elongation nucleotide pocket.

Citation: Liu Y, He Y, Molla A. 2009. Hepatitis C Virus Polymerase as a Target for Antiviral Drug Intervention: Non-Nucleoside Inhibitors, p 137-151. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch8
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Image of Figure 3.
Figure 3.

Structures of non-nucleoside inhibitors binding to the initiation nucleotide pocket.

Citation: Liu Y, He Y, Molla A. 2009. Hepatitis C Virus Polymerase as a Target for Antiviral Drug Intervention: Non-Nucleoside Inhibitors, p 137-151. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch8
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Image of Figure 4.
Figure 4.

Structures of non-nucleoside inhibitors binding to the lower thumb pocket.

Citation: Liu Y, He Y, Molla A. 2009. Hepatitis C Virus Polymerase as a Target for Antiviral Drug Intervention: Non-Nucleoside Inhibitors, p 137-151. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch8
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Image of Figure 5.
Figure 5.

Structures of non-nucleoside inhibitors binding to the upper thumb pocket.

Citation: Liu Y, He Y, Molla A. 2009. Hepatitis C Virus Polymerase as a Target for Antiviral Drug Intervention: Non-Nucleoside Inhibitors, p 137-151. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch8
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Image of Figure 6.
Figure 6.

Long-term replicon RNA inhibition by the combination of A-782759 and BILN-2061. Long-term RNA dynamics, passages 0 to 5. After passage 5, cell populations treated with 10× EC of either A-782759 or BILN-2061 were grown for 3 weeks in the absence of the antiviral compounds in the media containing 400-Mg/ml G418. The follow-up time point represents replicon RNA levels in the resistant cell population. Replicon RNA change, log change from the baseline caused by the antiviral treatments. (Reprinted from with permission of the publisher.)

Citation: Liu Y, He Y, Molla A. 2009. Hepatitis C Virus Polymerase as a Target for Antiviral Drug Intervention: Non-Nucleoside Inhibitors, p 137-151. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch8
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Tables

Generic image for table
Table 1.

Conservation of NS5B residues related to drug resistance

Citation: Liu Y, He Y, Molla A. 2009. Hepatitis C Virus Polymerase as a Target for Antiviral Drug Intervention: Non-Nucleoside Inhibitors, p 137-151. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch8
Generic image for table
Table 2.

Resistant mutants against non-nucleoside inhibitors of NS5B RNA-dependent RNA polymerase

Citation: Liu Y, He Y, Molla A. 2009. Hepatitis C Virus Polymerase as a Target for Antiviral Drug Intervention: Non-Nucleoside Inhibitors, p 137-151. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch8

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