Chemistry Reference
In-Depth Information
HCV is a single-stranded, positive sense RNA virus in the Flaviviridea virus
family.
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There are six major viral genotypes and over 50 viral subtypes,
demonstrating significant genomic sequence diversity.
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The broad genotype
diversity results from what is believed to be poor replicative fidelity associated
with the HCV RNA-dependent RNA polymerase. In the Western world,
genotypes 1a and 1b are the most common genotypes, with genotypes 2 and 3
comprising 20-30% of the total reported cases. In the developing world, geno-
types 2-6 predominate. The genotype diversity and poor replicative fidelity
associated with HCV has made the identification of a vaccine di
cult. Con-
sequently, efforts to identify anti-HCV agents have focused to a large extent on
identification of small molecules that act directly on the virus and inhibit its
ability to replicate.
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The hepatitis C virus is composed of a 9.6 kb plus strand RNA genome that
encodes 10 proteins, three structural proteins, and seven non-structural pro-
teins.
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The non-structural proteins have been the focus of intensive efforts to
identify novel and effective anti-HCV agents. One of these non-structural
proteins, the NS5B RNA-dependent RNA polymerase (RdRp), is particularly
attractive for the development of a direct-acting antiviral agent because it is
required for HCV replication.
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The HCV polymerase is part of a membrane-
associated replication complex that includes other viral proteins, viral RNA,
and altered cellular membranes. In concert with other non-structural proteins,
NS5B is responsible for replicating the viral RNA chain by catalyzing the
addition of nucleoside monophosphate building blocks to a growing RNA
chain that is a complementary copy of the existing RNA template strand. Since
NS5B is known to be devoid of a ''proofreading'' mechanism, HCV RNA
replication is assumed to be a highly error-prone process, resulting in a high
mutation rate. This high mutation rate can result in rapid emergence of drug-
resistant variants.
The HCV NS5B polymerase has the classic palm-finger-thumb domain
motif reminiscent of other viral polymerases.
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As with the development of
inhibitors of other viral polymerases, two approaches have been pursued to
identify small-molecule HCV NS5B polymerase inhibitors. The first approach
entails the identification of nucleoside derivatives that bind to the active site of
the polymerase and get incorporated into the growing RNA chain, thereby
inducing a chain termination event. The second approach leverages non-
nucleoside inhibitors that function by binding to allosteric sites on the NS5B
protein, thus preventing the polymerase from functioning effectively. In our
efforts to discover and develop an HCV inhibitor, we chose to pursue the
nucleoside strategy. Our choice was based on the long history of nucleosides as
the backbone therapy for the treatment of viral diseases, and the demonstrated
effectiveness of nucleosides as direct-acting antiviral agents for diseases such as
human immunodeficiency virus (HIV), hepatitis B virus (HBV), herpes virus,
and other viral diseases. In addition, nucleosides are attractive because of their
well-established development path and the wealth of knowledge available
pertaining to associated toxicological signals.
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