Nucleic Acids in Chemistry and Biology

dehydrogenase, resulting in a depletion of cellular GTP pools. This in turn means that ribavirin 5-triphosphate
is an effective competitive inhibitor of the viral-specific RNA polymerase for some viruses. Ribavirin
5 -triphosphate is also known to inhibit the viral-specific mRNA-capping enzymes, guanyl transferase and
N^7 -methyl transferase, so that viral protein synthesis is interrupted.

3.7.2.2.5 Phosphonoformic Acid. Phosphonoacetic acid(PAA, Figure 3.97a) was discovered to

have antiherpetic activity in vitrofollowing random screening in 1973. Two years later it was shown to be
a selective inhibitor of the virally encoded DNA polymerase, and the related phosphonoformic acid (PFA,
Figure 3.97b) was subsequently found to be an even stronger inhibitor of this enzyme. PFA (foscarnet,
Foscavir®) is used clinically for the treatment of CMV retinitis in AIDS patients. Both PAA and PFA are
analogues of pyrophosphate, a product of polymerases, and presumably bind to the corresponding site on
the enzyme and thus prevent replication. One problem with compounds of this sort is that they require no
prior activation and therefore the difference in affinity between the virus-encoded and the host-cell poly-
merase determines their effectiveness.
Hepatitis B virus has a partially double stranded DNA genome with an ORF that codes for a DNA poly-
merase that is also an RT. It thus presents a very focused target for anti-viral nucleoside development.
A wide range of nucleoside analogues have been used for HBV treatment (Table 3.2 and Figures 3.90 and
3.94) illustrating the breadth of modification to the 2-deoxy-D-ribose that has been explored by chemical
synthesis. They reveal that the DNA polymerase of HBV has a preference for the L- over the D-enantiomers
of some dNTP analogues, an advantage enhanced by the fact that L-enantiomers are often less toxic and
more stable to metabolism than their D-counterparts.
There is still much to be done in this area of research. The rational design of novel inhibitors will con-
tinue to rely on knowledge of the details of viral replication at the molecular level. The number of struc-
tures of important virus-target enzymes will steadily rise. But success in designing analogues that are
effective inhibitors in vitroand then converting such knowledge into a useful drug still calls for intact
delivery of the drug at an effective concentration to the desired location and with minimum toxicity. Orally
active forms of drugs are increasingly desirable for non-lethal infections.

References

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   Biochem., 2003, 270 , 1628–1644.


2. S. Verma and F. Eckstein, Modified oligonucleotides: synthesis and strategy for users. Ann. Rev.
   Biochem., 1998, 67 , 99–134.


3. B.E. Eaton and W.A. Pieken, Ribonucleosides and RNA. Ann. Rev. Biochem., 1995, 64 , 837–863.


4. E. Fischer and B. Helferich, Synthetische glucosine der purine. Chem. Ber., 1914, 47 , 210–235.


5. J. Davoll, A.R. Lythgoe and A.R. Todd, Experiments on the synthesis of purine nucleosides. Part XIX.
   A synthesis of adenosine. J. Chem. Soc., 1948, 967–969.


6. J. Davoll, A.R. Lythgoe and A.R. Todd, Experiments on the synthesis of purine nucleosides. Part XX.
   A synthesis of guanosine. J. Chem. Soc., 1948, 1685–1687.


7. J. Davoll and B.A. Lowy, A new synthesis of purine nucleosides. The synthesis of adenosine, guanosine
   and 2,6-diamino-9-
   -D-ribofuranosylpurine. J. Am. Chem. Soc., 1951, 73 , 1650–1655.

136 Chapter 3

O

PO

OO

O

O

P

OO

O

O

a b

PAA PFA

Figure 3.97 Anti-viral analogues of pyrophosphate. (a) Phosphonoacetic acid; (b) Phosphonoformic acid

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