Antiviral Drugs

Chemotherapy of Viral Infections
Viruses essentially consist of genetic
material (nucleic acids, green strands in
(A) and a capsular envelope made up of
proteins (blue hexagons), often with a
coat (gray ring) of a phospholipid (PL)
bilayer with embedded proteins (small
blue bars). They lack a metabolic system
but depend on the infected cell for their
growth and replication. Targeted therapeutic
suppression of viral replication
requires selective inhibition of those
metabolic processes that specifically
serve viral replication in infected cells.
To date, this can be achieved only to a
limited extent.
Viral replication as exemplified
by Herpes simplex viruses (A): (1) The
viral particle attaches to the host cell
membrane (adsorption) by linking its
capsular glycoproteins to specific structures
of the cell membrane. (2) The viral
coat fuses with the plasmalemma of the
host cell and the nucleocapsid (nucleic
acid plus capsule) enters the cell interior
(penetration). (3) The capsule opens
(“uncoating”) near the nuclear pores
and viral DNA moves into the cell nucleus.
The genetic material of the virus can
now direct the cell’s metabolic system.
(4a) Nucleic acid synthesis: The genetic
material (DNA in this instance) is replicated
and RNA is produced for the purpose
of protein synthesis. (4b) The proteins
are used as “viral enzymes” catalyzing
viral multiplication (e.g., DNA
polymerase and thymidine kinase), as
capsomers, or as coat components, or
are incorporated into the host cell
membrane. (5) Individual components
are assembled into new virus particles
(maturation). (6) Release of daughter viruses
results in spread of virus inside
and outside the organism. With herpes
viruses, replication entails host cell destruction
and development of disease
symptoms.
Antiviral mechanisms (A). The organism
can disrupt viral replication
with the aid of cytotoxic T-lymphocytes
that recognize and destroy virus-producing
cells (viral surface proteins) or
by means of antibodies that bind to and
inactivate extracellular virus particles.
Vaccinations are designed to activate
specific immune defenses.
Interferons (IFN) are glycoproteins
that, among other products, are released
from virus-infected cells. In
neighboring cells, interferon stimulates
the production of “antiviral proteins.”
These inhibit the synthesis of viral proteins
by (preferential) destruction of viral
DNA or by suppressing its translation.
Interferons are not directed against
a specific virus, but have a broad spectrum
of antiviral action that is, however,
species-specific. Thus, interferon for use
in humans must be obtained from cells
of human origin, such as leukocytes
(IFN-α), fibroblasts (IFN-β), or lymphocytes
(IFN-γ). Interferons are also used
to treat certain malignancies and autoimmune
disorders (e.g., IFN-α for chronic
hepatitis C and hairy cell leukemia;
IFN-β for severe herpes virus infections
and multiple sclerosis).
Virustatic antimetabolites are
“false” DNA building blocks (B) or nucleosides.
A nucleoside (e.g., thymidine)
consists of a nucleobase (e.g., thymine)
and the sugar deoxyribose. In antimetabolites,
one of the components is defective.
In the body, the abnormal nucleosides
undergo bioactivation by attachment
of three phosphate residues
(p. 287).
Idoxuridine and congeners are incorporated
into DNA with deleterious
results. This also applies to the synthesis
of human DNA. Therefore, idoxuridine
and analogues are suitable only for topical
use (e.g., in herpes simplex keratitis).
Vidarabine inhibits virally induced
DNA polymerase more strongly than it
does the endogenous enzyme. Its use is
now limited to topical treatment of severe
herpes simplex infection. Before
the introduction of the better tolerated
acyclovir, vidarabine played a major
part in the treatment of herpes simplex
encephalitis.
Among virustatic antimetabolites,
acyclovir (A) has both specificity of the
highest degree and optimal tolerability,


because it undergoes bioactivation only
in infected cells, where it preferentially
inhibits viral DNA synthesis. (1) A virally
coded thymidine kinase (specific to H.
simplex and varicella-zoster virus) performs
the initial phosphorylation step;
the remaining two phosphate residues
are attached by cellular kinases. (2) The
polar phosphate residues render acyclovir
triphosphate membrane impermeable
and cause it to accumulate in infected
cells. (3) Acyclovir triphosphate
is a preferred substrate of viral DNA
polymerase; it inhibits enzyme activity
and, following its incorporation into viral
DNA, induces strand breakage because
it lacks the 3’-OH group of deoxyribose
that is required for the attachment
of additional nucleotides. The high
therapeutic value of acyclovir is evident
in severe infections with H. simplex viruses
(e.g., encephalitis, generalized infection)
and varicella-zoster viruses
(e.g., severe herpes zoster). In these cases,
it can be given by i.v. infusion. Acyclovir
may also be given orally despite
its incomplete (15%–30%) enteral absorption.
In addition, it has topical uses.
Because host DNA synthesis remains
unaffected, adverse effects do not include
bone marrow depression. Acyclovir
is eliminated unchanged in urine
(t1/2 ~ 2.5 h).
Valacyclovir, the L-valyl ester of
acyclovir, is a prodrug that can be administered
orally in herpes zoster infections.
Its absorption rate is approx.
twice that of acyclovir. During passage
through the intestinal wall and liver, the
valine residue is cleaved by esterases,
generating acyclovir.
Famcyclovir is an antiherpetic prodrug
with good bioavailability when
given orally. It is used in genital herpes
and herpes zoster. Cleavage of two acetate
groups from the “false sugar” and
oxidation of the purine ring to guanine
yields penciclovir, the active form. The
latter differs from acyclovir with respect
to its “false sugar” moiety, but mimics it
pharmacologically. Bioactivation of
penciclovir, like that of acyclovir, involves
formation of the triphosphorylated
antimetabolite via virally induced
thymidine kinase.
Ganciclovir (structure on p. 285) is
given by infusion in the treatment of severe
infections with cytomegaloviruses
(also belonging to the herpes group);
these do not induce thymidine kinase,
phosphorylation being initiated by a
different viral enzyme. Ganciclovir is
less well tolerated and, not infrequently,
produces leukopenia and thrombopenia.
Foscarnet represents a diphosphate
analogue.
As shown in (A), incorporation of
nucleotide into a DNA strand entails
cleavage of a diphosphate residue. Foscarnet
(B) inhibits DNA polymerase by
interacting with its binding site for the
diphosphate group. Indications: systemic
therapy of severe cytomegaly infection
in AIDS patients; local therapy of
herpes simplex infections.
Amantadine (C) specifically affects
the replication of influenza A (RNA) viruses,
the causative agent of true influenza.
These viruses are endocytosed
into the cell. Release of viral DNA requires
protons from the acidic content
of endosomes to penetrate the virus.
Presumably, amantadine blocks a channel
protein in the viral coat that permits
influx of protons; thus, “uncoating” is
prevented. Moreover, amantadine inhibits
viral maturation. The drug is also
used prophylactically and, if possible,
must be taken before the outbreak of
symptoms. It also is an antiparkinsonian



Drugs for the Treatment of AIDS
Replication of the human immunodeficiency
virus (HIV), the causative
agent of AIDS, is susceptible to targeted
interventions, because several virusspecific
metabolic steps occur in infected
cells (A). Viral RNA must first be transcribed
into DNA, a step catalyzed by viral
“reverse transcriptase.” Doublestranded
DNA is incorporated into the
host genome with the help of viral integrase.
Under control by viral DNA, viral
replication can then be initiated, with
synthesis of viral RNA and proteins (including
enzymes such as reverse transcriptase
and integrase, and structural
proteins such as the matrix protein lining
the inside of the viral envelope).
These proteins are assembled not individually
but in the form of polyproteins.
These precursor proteins carry an N-terminal
fatty acid (myristoyl) residue that
promotes their attachment to the interior
face of the plasmalemma. As the virus
particle buds off the host cell, it carries
with it the affected membrane area
as its envelope. During this process, a
protease contained within the polyprotein
cleaves the latter into individual,
functionally active proteins.
I. Inhibitors of Reverse Transcriptase
IA. Nucleoside agents
These substances are analogues of thymine
(azidothymidine, stavudine),
adenine (didanosine), cytosine (lamivudine,
zalcitabine), and guanine (carbovir,
a metabolite of abacavir). They
have in common an abnormal sugar
moiety. Like the natural nucleosides,
they undergo triphosphorylation, giving
rise to nucleotides that both inhibit reverse
transcriptase and cause strand
breakage following incorporation into
viral DNA.
The nucleoside inhibitors differ in
terms of l) their ability to decrease circulating
HIV load; 2) their pharmacokinetic
properties (half life ! dosing
interval ! compliance; organ distribution
!passage through blood-brainbarrier);
3) the type of resistance-inducing
mutations of the viral genome and the
rate at which resistance develops; and
4) their adverse effects (bone marrow
depression, neuropathy, pancreatitis).
IB. Non-nucleoside inhibitors
The non-nucleoside inhibitors of reverse
transcriptase (nevirapine, delavirdine,
efavirenz) are not phosphorylated.
They bind to the enzyme with
high selectivity and thus prevent it from
adopting the active conformation. Inhibition
is noncompetitive.
II. HIV protease inhibitors
Viral protease cleaves precursor proteins
into proteins required for viral
replication. The inhibitors of this protease
(saquinavir, ritonavir, indinavir,
and nelfinavir) represent abnormal
proteins that possess high antiviral efficacy
and are generally well tolerated in
the short term. However, prolonged administration
is associated with occasionally
severe disturbances of lipid and
carbohydrate metabolism. Biotransformation
of these drugs involves cytochrome
P450 (CYP 3A4) and is therefore
subject to interaction with various other
drugs inactivated via this route.
For the dual purpose of increasing
the effectiveness of antiviral therapy
and preventing the development of a
therapy-limiting viral resistance, inhibitors
of reverse transcriptase are combined
with each other and/or with protease
inhibitors.
Combination regimens are designed
in accordance with substancespecific
development of resistance and
pharmacokinetic parameters (CNS
penetrability, “neuroprotection,” dosing
frequency).