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CASE FILES: BIOCHEMISTRY
of DNA form base pairs with complementary base sequences on another
strand of DNA or RNA. During replication, repair and transcription, complex
proteins (helicases during DNA replication, RNA polymerase during tran-
scription) cause the separation of the two strands.
The
cellular DNA and RNA polymerases
of higher organisms are much
more accurate than those of viruses because of their high specificities and, in the
case of DNA polymerases, proofreading capabilities. This accounts for the high
degree of mutation in viruses. However, this can have therapeutic advantages.
Ribavirin
(1-P-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) is a
purine nucleoside analog
exhibiting in vitro antiviral activity against a broad
spectrum of DNA and RNA viruses. Ribavirin has shown clinical efficacy
against both influenza A and B viruses. This antiviral activity is a result of the
resemblance of this compound to nucleosides.
Studies showed that ribavirin
most closely
resembles guanosine,
as determined by x-ray crystallography
(Figure 2-1). Once in cells, ribavirin is converted to its 5'-phosphate deriva-
tives by cellular enzymes. The major metabolite is ribavirin-5'-triphosphate
(RTP), and the intracellular concentration of the mono-, di-, and triphosphate
derivatives probably is similar to that of other cellular nucleotides. Although
not all polymerase/replication systems use ribavirin as they do guanosine, it
has been shown that many of the systems that are inhibited by ribavirin are
reversed by the addition of guanosine.
Until 2001, it was thought that the mechanism of action of ribavirin
involved a decrease in cellular guanosine triphosphate (GTP) pools result-
ing from inhibition of inosine monophosphate dehydrogenase by ribavirin
monophosphate. More recently, the mechanism of action for ribavirin has
been expanded to include lethal mutagenesis of the viral genome as a result of
ribavirin triphosphate utilization by the error-prone viral RNA-dependent
RNA polymerase, and incorporation of ribavirin into viral RNA.
Figure 2-1.
Comparison of the structures of ribavirin (1-ß-D-ribofuranosyl-
1H-1,2,4-triazole-3-carboxamide) with the purine nucleoside guanosine.
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