Nucleic Acids in Chemistry and Biology

viral infections, such as HIV. For example, the anti-AIDS drug AZT (Figure 3.90) was marketed within a
year of the report of its in vitro properties.

3.7.2.2 Anti-DNA Virus Drug Design. Herpesviruses are double-stranded DNA viruses that cause

a variety of diseases in humans: cold sores, eye infections (keratitis), genital sores, chickenpox, shingles
and glandular fever (infectious mononucleosis). They all exhibit latency, which means that following
infection of a cell, the virus produced can go into a latent state in nerve endings from where it can be reacti-
vated by various stimuli (stress, UV light, other viral infections, etc.). Since it has so far been impossible
to destroy the virus in the latent state (i.e.prevent it from replicating), antiviral chemotherapy must be
directed first against primary infection and then against subsequent recurrent episodes.
Herpesviruses code for many enzymes involved in their own replication and metabolism. These are suf-
ficiently different from the corresponding ones in the host cell to give an opportunity for selective inter-
ference. For example, HSVs rely largely on the salvage pathway for the production of dTTP for DNA
synthesis and so the viruses encode their own thymidine kinase, TK. The specificity of the viral TK is not
as great as that of the host cell and it phosphorylates a wide range of nucleoside analogues that, once acti-
vated, inhibit viral replication. HSVs also code for their own DNA polymerase, which has a different speci-
ficity from the cellular polymerases and hence presents a target for selective attack.

3.7.2.2.1 Acyclovir and Related Acyclonucleosides.^133 Acyclovir (Figure 3.92) is effective

against HSVs, and its metabolic conversion into the active form is remarkable. Although acyclovir is a
purine nucleoside analogue lacking C-2and C-3of the sugar ring, it is specifically phosphorylated at the
position equivalent to the 5-hydroxyl group by the thymidine kinase of the HSV. Not surprisingly, no such
metabolism occurs in an uninfected cell. However, in the virally infected cell, 5-phosphorylated acyclovir
is now recognised by the host-cell guanylate kinase and is taken to the diphosphate, from which a nucleo-
side diphosphate kinase produces the 5-triphosphate. This is now a substrate for the HSV-encoded DNA
polymerase and it is incorporated into viral DNA. Since the analogue has no 3-hydroxyl group, it is a
chain terminator and thus stops the synthesis of viral DNA (Figure 3.92).
Developments aimed at enhancing the oral bioavailability of acyclovir have resulted in the discovery of
valaciclovir (Figure 3.93), the L-valyl ester of acyclovir. This acts as prodrug of the parent nucleoside and,
as it has increased solubility, up to threefold higher plasma levels of acyclovir can be achieved.
The acyclonucleoside ganciclovir(Figure 3.93) is active against both HSV and cytomegalovirus (CMV)
infections. In the latter case, the initial phosphorylation is carried out by a CMV-encoded protein kinase.

Nucleosides and Nucleotides 133

O

O Gua

P

O

P

O

P

O

OOOOO O

O

HO Gua

O

O Gua

P

O

P

O

OOOO

O

O Gua

P

O

OO

viral thymidine kinase

nucleoside

diphosphate

kinase

acyclovir

GMP

kinase

acyclovir triphosphate

Figure 3.92 Enzymatic phosphorylation of acyclovir