DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 58–1
Stages of Virus Replication and Possible Targets of Action of Antiviral Agents
STAGE OF REPLICATION
CLASSES OF SELECTIVE INHIBITORS
Cell entry
Attachment
Soluble receptor decoys, antireceptor antibodies, fusion protein inhibitors
Penetration
Uncoating
Ion channel blockers, capsid stabilizers
Release of viral genome
Transcription of viral genome a
Inhibitors of viral DNA polymerase, RNA polymerase, reverse
Transcription of viral messenger RNA transcriptase, helicase, primase, or integrase
Replication of viral genome
Translation of viral proteins
Interferons, antisense oligonucleotides, ribozymes
Regulatory proteins (early)
Inhibitors of regulatory proteins
Structural proteins (late)
Post-translational modifications
Proteolytic cleavage
Protease inhibitors
Myristoylation, glycosylation
Assembly of virion components
Interferons, assembly protein inhibitors
Release
Neuraminidase inhibitors, antiviral antibodies, cytotoxic lymphocytes
Budding, cell lysis
a
Depends on specific replication strategy of virus, but virus-specified enzyme required for part of process.
hands, or meninges. Both cause serious infections in
neonates. HSV infection may be a primary one in a
naive host, a nonprimary initial one in a host previously
infected by other viruses, or the consequence of activation
of a latent infection.
The first systemically administered anti-herpesvirus
agent, vidarabine (no longer marketed in the U.S.), was
approved by the FDA in 1977. However, toxicities
restricted its use to life- or vision-threatening infections
of HSV and varicella-zoster virus (VZV). The discovery
and development of acyclovir, approved in 1982, provided
the first effective treatment for less severe HSV
and VZV infections in ambulatory patients. Intravenous
acyclovir is superior to vidarabine in terms of efficacy
and toxicity in HSV encephalitis and in VZV infections
of immunocompromised patients. Acyclovir is the prototype
of a group of antiviral agents that are phosphorylated
intracellularly by a viral kinase and subsequently
by host cell enzymes to become inhibitors of viral DNA
synthesis. Other agents employing this strategy include
penciclovir and ganciclovir.
Acyclovir and Valacyclovir
Chemistry and Antiviral Activity. Acyclovir is an acyclic
guanine nucleoside analog that lacks a 3′-hydroxyl on the
side chain. Valacyclovir is the L-valyl ester prodrug of
acyclovir. Acyclovir and valacyclovir chemical structures
are depicted in Figure 58–2.
Acyclovir’s clinically useful antiviral spectrum
is limited to herpesviruses. In vitro, acyclovir is most
active against HSV-1 (0.02-0.9 μg/mL), approximately
half as active against HSV-2 (0.03-2.2 μg/mL),
a tenth as potent against VZV (0.8-4.0 μg/mL) and
Epstein-Barr virus (EBV), and least active against
cytomegalovirus (CMV) (generally >20 μg/mL) and
human herpesvirus 6 (HHV-6). Uninfected mammalian
cell growth generally is unaffected by high acyclovir concentrations
(>50 μg/mL).
Mechanisms of Action and Resistance. Acyclovir
inhibits viral DNA synthesis via a mechanism outlined
in Figure 58–3 (Elion, 1986). Its selectivity of action
depends on interaction with two distinct viral proteins:
HSV thymidine kinase and DNA polymerase. Cellular
uptake and initial phosphorylation are facilitated by
HSV thymidine kinase. The affinity of acyclovir for
HSV thymidine kinase is ~200 times greater than for
the mammalian enzyme. Cellular enzymes convert the
monophosphate to acyclovir triphosphate, which is
present in 40-100-fold higher concentrations in HSVinfected
than in uninfected cells and competes for
endogenous deoxyguanosine triphosphate (dGTP).