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Chapter 9 : Nucleoside Analog Inhibitors of Hepatitis C Viral Replication
Authors:
Steven S. Carroll1,
Robert L. LaFemina2
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Affiliations:
1: Antiviral Research, Merck Research Laboratories, West Point, PA 19486;
2: 2020 Serendipity Way, Schwenksville, PA 19473
Content Type: Monograph
Publication Year:
2009
Category: Viruses and Viral Pathogenesis; Clinical Microbiology
Book DOI:
10.1128/9781555815493
Chapter DOI:
10.1128/9781555815493.ch9
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Nucleoside Analog Inhibitors of Hepatitis C Viral Replication, Page 1 of 2
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Abstract:
The discovery of an infectious virus system based on virus from a patient with fulminant hepatitis has created another tool for investigating the viral replication cycle. All of the nucleoside drugs used to treat infections with human immunodeficiency virus (HIV), hepatitis B virus, and herpesviruses can be considered to be 29-deoxynucleoside analogs. Since its nucleotide substrates are ribonucleotides, Hepatitis C virus (HCV) RNA polymerase novel has different substrate specificity regarding substituents at the 29 position of the ribose ring. Thus, it is likely that substituents at the 2' position of the ribose ring of nucleoside analog inhibitors of RNA polymerase that give rise to potent inhibition will be different from those active as inhibitors of DNA polymerase activity. Inhibition of HCV replication at other putative sites of replication such as lymphocytes may also be important to achieve viral clearance. Roche has disclosed the discovery of nucleoside analog inhibitors of HCV replication having modifications at the 4' position. Ribavirin (1-b-d-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a nucleoside analog with a long history of use as a chemotherapy to treat viral infection with a broad spectrum of activity. Liver biopsy showed hepatic pathogenesis typical of HCV infection. Reisolation of virus used to infect new chimps showed that the H77 strain was infectious in subsequent recipient chimps. It is more difficult to address ribavirin resistance in cell culture because ribavirin is not a very effective replication inhibitor of 1b replicons. Since nucleoside analogs must be converted to the triphosphate, they are inherently prodrugs.
Citation:
Carroll S, LaFemina R.
2009.
Nucleoside Analog Inhibitors of Hepatitis C Viral Replication,
p 153-166.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch9
Figures
Nucleoside Analog Inhibitors of Hepatitis C Viral Replication
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Citation:
Carroll S, LaFemina R.
2009.
Nucleoside Analog Inhibitors of Hepatitis C Viral Replication,
p 153-166.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch9
/content/10.1128/9781555815493.ch09.ch09fig01
Figure 1.
Structures of nucleoside analogs.
10.1128/9781555815493/f0155-01_thmb.gif
10.1128/9781555815493/f0155-01.gif
Figure 1.
Structures of nucleoside analogs.
Citation:
Carroll S, LaFemina R.
2009.
Nucleoside Analog Inhibitors of Hepatitis C Viral Replication,
p 153-166.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch9
/content/10.1128/9781555815493.ch09.ch09fig02
Figure 2.
The organization of the HCV genome is shown on top. Nontranslated RNAs (NTR) are shown as lines with stem-loop structures indicated. The 5’ NTR acts as IRES. The protein coding regions are boxed, and the length of the box indicates the relative size of the mature protein. Proteins in order from left to right are the structural region proteins core (C), envelope glycoproteins E1 and E2, p7, and nonstructural proteins NS2, 3, 4A, 4B, 5A, and 5B. The 3’ nontranslated region consists of a variable sequence (N), a pyrimidine tract (U/C), and a C-terminal 98-base sequence. Host cell peptidase cleavage sites within the structural region are indicated by arrowheads below the boxes. The NS2/3 protease cleavage site is indicated by the slanted arrow above the box, and NS3/4A protease cleavages sites are indicated by the vertical arrows above the nonstructural coding region. The organization of the HCV NS3 replicon is shown on bottom. Neor indicates the selectable neomycin phosphotransferase coding region, which is part of a fusion protein with the N terminus of the core protein (Cn). In reporter replicons used in transient assays, this is replaced by a reporter gene. The location of the encephalomyocarditis virus IRES is indicated by the straight line without regard to secondary structure. Four variants of the replicon were originally described by Lohmann et al. (
43
), consisting of two versions of the truncated core fused to neomycin phosphotransferase and nonstructural sequences with or without the NS2 coding region. Only the NS3 variant is shown. The figure is redrawn and modified from reference
38
.
10.1128/9781555815493/f0160-01_thmb.gif
10.1128/9781555815493/f0160-01.gif
Figure 2.
The organization of the HCV genome is shown on top. Nontranslated RNAs (NTR) are shown as lines with stem-loop structures indicated. The 5’ NTR acts as IRES. The protein coding regions are boxed, and the length of the box indicates the relative size of the mature protein. Proteins in order from left to right are the structural region proteins core (C), envelope glycoproteins E1 and E2, p7, and nonstructural proteins NS2, 3, 4A, 4B, 5A, and 5B. The 3’ nontranslated region consists of a variable sequence (N), a pyrimidine tract (U/C), and a C-terminal 98-base sequence. Host cell peptidase cleavage sites within the structural region are indicated by arrowheads below the boxes. The NS2/3 protease cleavage site is indicated by the slanted arrow above the box, and NS3/4A protease cleavages sites are indicated by the vertical arrows above the nonstructural coding region. The organization of the HCV NS3 replicon is shown on bottom. Neor indicates the selectable neomycin phosphotransferase coding region, which is part of a fusion protein with the N terminus of the core protein (Cn). In reporter replicons used in transient assays, this is replaced by a reporter gene. The location of the encephalomyocarditis virus IRES is indicated by the straight line without regard to secondary structure. Four variants of the replicon were originally described by Lohmann et al. ( 43 ), consisting of two versions of the truncated core fused to neomycin phosphotransferase and nonstructural sequences with or without the NS2 coding region. Only the NS3 variant is shown. The figure is redrawn and modified from reference 38 .
Citation:
Carroll S, LaFemina R.
2009.
Nucleoside Analog Inhibitors of Hepatitis C Viral Replication,
p 153-166.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch9
/content/10.1128/9781555815493.ch09.ch09fig03
Figure 3.
Shift in inhibitory potency for different classes of inhibitors of the HCV RNA polymerases from different genotypes. Non-nucleoside inhibitor structural classes, indole acetamides (
31
), thiophenes (
18
), and thiadiazines (
23
), show greater variability in potency than does the 2’-C-methyl nucleoside analog (
13
).
10.1128/9781555815493/f0162-01_thmb.gif
10.1128/9781555815493/f0162-01.gif
Figure 3.
Shift in inhibitory potency for different classes of inhibitors of the HCV RNA polymerases from different genotypes. Non-nucleoside inhibitor structural classes, indole acetamides ( 31 ), thiophenes ( 18 ), and thiadiazines ( 23 ), show greater variability in potency than does the 2’-C-methyl nucleoside analog ( 13 ).
Citation:
Carroll S, LaFemina R.
2009.
Nucleoside Analog Inhibitors of Hepatitis C Viral Replication,
p 153-166.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch9
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