Antiviral drugs

• Antiviral drugs are a class of medication used specifically for treating viral infections.
– Like antibiotics for bacteria, specific antivirals are used for specific viruses.
– Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead
they inhibit their development.
• Antiviral drugs are one class of antimicrobials, a larger group which also includes
antibiotic, antifungal and antiparasitic drugs.
– They are relatively harmless to the host, and therefore can be used to treat infections.
– They should be distinguished from viricides, which are not medication but destroy virus
particles outside the body.
• Most of the antivirals now available are designed to help deal with
– HIV
– Herpes viruses
– Hepatitis B and C viruses
– Influenza A and B viruses.
• Designing safe and effective antiviral drugs is difficult, because viruses use the host's
cells to replicate.
– This makes it difficult to find targets for the drug that would interfere with the virus without
also harming the host organism's cells.
• The emergence of antivirals is the product of a greatly expanded knowledge of the
genetic and molecular function of organisms, allowing biomedical researchers to
understand the structure and function of viruses, major advances in the techniques
for finding new drugs, and the intense pressure placed on the medical profession to
deal with the human immunodeficiency virus (HIV), the cause of the deadly acquired
immunodeficiency syndrome (AIDS) pandemic.
• Almost all anti-microbials, including anti-virals, are subject to drug resistance as the
pathogens mutate over time, becoming less susceptible to the treatment.
– A recent study published in Nature Biotechnology emphasized the urgent need for
augmentation of oseltamivir (Tamiflu) stockpiles with additional antiviral drugs including
zanamivir (Relenza) based on an evaluation of the performance of these drugs in the
scenario that the 2009 H1N1 'Swine Flu' neuraminidase (NA) were to acquire the tamiflu-
resistance (His274Tyr) mutation which is currently widespread in seasonal H1N1 strains.
 History

• Through the mid- to late-20th century, medical

science and practice included an array of
effective tools, ranging from antiseptics to
vaccines and antibiotics, but no drugs to treat
viral infections.
• While vaccines were effective in preventing
many viral diseases, they could not help once a
viral infection set in.
• Prior to the development of antivirals, when
someone contracted a virus, there was little that
could be done other than treating the symptoms
and waiting for the disease to run its course.
• The first experimental antivirals were developed
in the 1960s, mostly to deal with herpes viruses,
and were found using traditional trial-and-error
drug discovery methods.
– Researchers grew cultures of cells and infected
them with the target virus.
– They then introduced chemicals into the cultures
they thought were likely to inhibit viral activity, and
observed whether the level of virus in the cultures
rose or fell.
– Chemicals that seemed to have an effect were
selected for closer study.
• This was a very time-consuming, hit-or-miss
procedure, and in the absence of a good
knowledge of how the target virus worked, it was
not efficient in discovering antivirals that were
effective and had few side effects.
• It was not until the 1980s, when the full
genetic sequences of viruses began to be
unraveled, that researchers began to learn how
viruses worked in detail, and exactly what
chemicals were needed to thwart their
reproductive cycle. Dozens of antiviral
treatments are now available, and medical
research is rapidly exploiting new knowledge
and technology to develop more.
 Virus life cycle

• Viruses consist of a genome and sometimes a few

enzymes stored in a capsule made of protein
(called a capsid), and sometimes covered with a
lipid layer (called an 'envelope').
• Viruses cannot reproduce on their own, so they
propagate by subjugating a host cell to produce
copies of themselves, thus producing the next
generation.
• Researchers working on such "
rational drug design" strategies for developing
antivirals have tried to attack viruses at every
stage of their life cycles. Some species of
mushrooms have been found to contain multiple
antiviral chemicals with similar synergistic effects.
• Viral life cycles vary in their precise details
depending on the species of virus, but they all
share a general pattern:
– Attachment to a host cell.
– Release of viral genes and possibly enzymes
into the host cell.
– Replication of viral components using host-cell
machinery.
– Assembly of viral components into complete
viral particles.
– Release of viral particles to infect new host
cells.
 Viral life cycles
• Viral life cycles have several
specific steps, many of which
are targets for antiviral drugs.
• After virus adsorption,
enveloped viruses enter the cell
by virus–cell fusion.
– For human immunodeficiency
virus (HIV), which is a retrovirus
with an RNA (yellow) genome,
replication of the genome occurs
after reverse transcription and
integration into the host cell
chromosome.
– For DNA viruses, such as
herpesviruses, the genome is
replicated by a viral DNA
polymerase.
• After transcription to RNA,
followed by translation and
proteolytic processing of the
precursor polypeptide, viral
proteins assemble at the cell
membrane, from which they bud
to release new virions
 The life cycle of the
hepatitis C virus
(HCV)
• The life cycle of the hepatitis
C virus (HCV) has several
specific steps, many of which
are targets for antiviral drugs:
– a - attachment;
– b - endocytosis;
– c - virion– membrane
fusion;
– d - uncoating;
– e - translation and
polyprotein processing;
– f - replicase assembly;
– g - RNA replication;
– h - viral assembly and
ER budding;
– i - vesicle transport and
glycoprotein maturation;
– j - vesicle fusion and
virion release.
*ER - endoplasmic reticulum;
IRES - internal ribosome-entry site;
LDLR - low-density lipoprotein receptor;
NS - non-structural protein;
siRNA - small interfering RNA
The structure and
function of a virus

• Once attached to
its specific target
cell, virus injects
its DNA (or RNA)
into the host cell.
• Once inside the
'infected' cell, this
viral DNA (or RNA)
replicates itself as
well as using the
existing machinery
within the 'infected'
cell to make more
viral proteins.
• It then assembles
itself and can now
leave this cell to
infect other cells.
The structure and workings
of DNA (or RNA)
• All the DNA strand consists of are 5-carbon
deoxyribose (or ribose) sugars linked together
by phosphate groups.
– Additionally, each 5-carbon sugar has one of four
possible bases attached: A, G, C, or T.
– So in order to elongate a strand of DNA (or RNA),
the cell simply links the 'sugar-base-phosphate'
unit onto the existing 'sugar-base-phosphate' units
already linked together forming the strand of DNA.
– We oversimplify this by saying that the DNA strand
grows by adding additional bases.
• For example, our simplified explanation says
that the DNA strand grows by adding an "A", or
"G", or "C", or "T" base, one at a time.
• Remember that this "A", or "G" or "C" or "T" is
the 'sugar-base-phosphate' unit with the base
being either A, G, C, or T.
• This is an oversimplified but essentially
accurate explanation of how several antiviral
drugs work.
– The antiviral drug will be incorporated into the
growing DNA (or RNA) strand as if it were another
'sugar-base-phosphate' unit.
– Once this drug is incorporated into the growing
DNA strand, no other 'sugar-base-phosphate' units
can be attached, and so any further grows stops.
Hence, terminating the growth of viral DNA within
the infected cell.
• Acyclovir is an antiviral drug for herpes simplex
infection.
– Acyclovir is an analog of 2-deoxyguanosine ("G").
– The acyclovir is in fact modified by enzymes made
only by the virus so that the acyclovir can now be
incorporated into the growing viral DNA strand
instead of the "G".
– Once incorporated, any further elongation stops
because unlike "G" that should be there, the
acyclovir cannot attach any further nucleoties
(acyclovir cannot attach any further "A"'s, or "G"'s,
or "C"'s, or "T"'s).
• A herpes simplex virus attaches to a susceptible host cell (seen on
the right), fusing its envelope with the cell membrane, and releasing
naked capsids that deliver viral DNA into the nucleus of the host cell,
where it initiates the synthesis of viral DNA.
• Acyclovir molecules entering the cell are converted to acyclovir
monophosphate by virus induced thymidine kinase enzyme.
Host-cell enzymes add two more phosphates to form acyclovir
triphosphate, which is transported to the nucleus.
Shown in red is the cleavage of phosphate from the acyclovir
triphosphate by the herpes simplex's own enzymes, the herpes
simplex's DNA polymerase enzyme incorporates the acyclovir
monophosphate into the growing DNA strand as if it were 2-
deoxyguanosine monophosphate (a "G" base).
• Further elongation of the chain is impossible because acyclovir
monophosphate lacks the attachment point necessary for the
insertion of any additional nucleotides.
• I. The acyclovir (as do other antiviral drugs) is mistakenly
incorportated into the growing DNA strand. The enzymes adding in
"A"'s, or "G"'s, or "C"'s, or "T"'s recognize acyclovir as a "G" and add
it in.
• II. The acyclovir does not have the proper structure to add any
additional "A"'s, or "G"'s, or "C"'s, or "T"'s to it, and so the DNA
strand cannot continue to elongate or grow. Once the acyclovir is
incorporated, any further growth of viral DNA is terminated.
• III. If I swallow my acyclovir drugs, isn't acyclovir going into all of my
cells, and blocking the growth (or replication) of all my cell's DNA,
not just the cells infected with virus? Not necessarily. As you read,
the conversion of the original acyclovir into the form that is
incorporated into the DNA is carried out by the virus's own enzyme.
Therefore, only those cells that are infected with the virus will have
this specific enzyme and convert the original acyclovir into the
acyclovir that can be incorporated as a "G" base. Also, only the cells
infected with virus have the enzyme that mistakenly recognizes
acyclovir as a "G" base and puts it into the growing DNA strand. So,
again, all of your non-virally infected cells will not that this viral
enzyme and so not put acyclovir into growing DNA.
• As new viruses emerge from the host
cell, they are coated in a layer of
glycolipid originating from the cell
membrane. Haemagglutinin receptors
from the virus are bound to these
glycolipids. Neuraminidase cleaves the
glycolipid from the haemagglutinin
thus releasing the virus completely
from the host cell.
• The surfaces of influenza viruses are
dotted with neuraminidase proteins.
Neuraminidase, an enzyme, breaks
the bonds that hold new virus particles
to the outside of an infected cell. Once
the enzyme breaks these bonds, this
sets free new viruses that can infect
other cells and spread infection.
Neuraminidase inhibitors block the
enzyme's activity and prevent new
virus particles from being released,
thereby limiting the spread of infection
 Induced fit of an

enzyme inhibitor

• The influenza neuraminidase

enzyme is blocked by antiviral
drugs.
• Subtypes of the enzyme exist and
are divided into two groups, which
differ in the conformation of their
active sites.
– A - A loop of amino acids (known as
the 150-loop) in the active sites of
group-2 enzyme subtypes is
arranged such that no
conformational changes occur in the
active site on binding of an inhibitor.
– B - For group-1 subtypes, the 150-
loop has a different conformation
from group-2 subtypes, exposing a
large cavity next to it.
– C - When an inhibitor binds to
group-1 subtypes, the 150-loop
adopts a conformation similar to that
of group-2 neuraminidases.
Entry inhibitor
• A very early stage of viral infection is viral entry, when the
virus attaches to and enters the host cell.
• A number of "entry-inhibiting" or "entry-blocking" drugs are
being developed to fight HIV.
• HIV most heavily targets the immune system's white blood
cells known as "helper T cells", and identifies these target
cells through T-cell surface receptors designated "CD4" and
"CCR5".
• Attempts to interfere with the binding of HIV with the CD4
receptor have failed to stop HIV from infecting helper T cells,
but research continues on trying to interfere with the binding
of HIV to the CCR5 receptor in hopes that it will be more
effective.
– These drugs block the interaction between the cellular receptors
and the antireceptor on the virus by binding to or altering the
receptor sites.
– Scientists have found that people who naturally lack these cellular
receptors because of a genetic mutation, or those who have them
blocked by natural chemokines (chemical messengers), may not
get infected as readily with HIV or may progress more slowly to
AIDS.
– Scientists are also examining vaccines that may help the body
block these receptors. 

Uncoating inhibitor
• Inhibitors of uncoating have also been investigated
• Amantadine and rimantadine, have been introduced to
combat influenza. These agents act on
penetration/uncoating.
• Pleconaril works against rhinoviruses, which cause the
common cold, by blocking a pocket on the surface of the
virus that controls the uncoating process.
– This pocket is similar in most strains of rhinoviruses and
enteroviruses, which can cause diarrhea, meningitis, conjunctivitis
, and encephalitis.
 Viral Penetration/Fusion
inhibitors

•
After attachment is completed, viral penetration
occurs.
• Penetration allows the nucleocapsid - the
genetic core - of the virus to be injected directly
into the cell's cytoplasm.
• gp120 actually contains three sugar-coated
proteins (glycoproteins) and, once gp120
attaches itself to CD4, these three proteins
spread apart.
• This allows the gp41 protein, which is normally
hidden by the gp120 proteins, to become
exposed and bind to the chemokine receptor.
• Once this has occurred, the viral envelope and
the cell membrane are brought into direct
contact and essentially melt into each other.
• Drugs called fusion inhibitors prevent the binding
of gp41 and the chemokine receptor.
• T-20 (Enfuvirtide, Fuzeon), an experimental
fusion inhibitor that is nearing FDA approval,
binds to a portion of gp41, preventing it from
binding to the chemokine receptor.
 Uncoating inhibitor
• Once HIV has penetrated the cell
membrane, it is ready to release its
genetic information (RNA) into the cell.
• The viral RNA is protected in the
nucleocapsid.
• The nucleocapsid needs to be partially
dissolved so that the virus's RNA can be
converted into DNA, a necessary step if
HIV's genetic material is to be
incorporated into the T-cell's genetic
core.
• Inhibitors of uncoating have also been
investigated
• Amantadine and rimantadine, have been
introduced to combat influenza. These
agents act on penetration/uncoating.
• Pleconaril works against rhinoviruses,
which cause the common cold, by
blocking a pocket on the surface of the
virus that controls the uncoating
process.
– This pocket is similar in most strains
of rhinoviruses and enteroviruses,
which can cause diarrhea,
meningitis, conjunctivitis, and
encephalitis.
 • The process by which HIV's RNA is converted to
Reverse Transcription DNA is called reverse transcription.
• This transcription process happens in almost
every human cell, but in the opposite direction
- from DNA to RNA.
• DNA from the cell nucleus is transcribed into
messenger RNA, which then directs the cell's
various metabolic functions needed to do its job in
the body.
• HIV uses an enzyme called reverse transcriptase
to accomplish this transcription.
• The single-stranded viral RNA is transcribed into a
double strand of DNA, which contains the
instructions HIV needs to hijack a T-cell's genetic
machinery in order to reproduce itself.
• Reverse transcriptase uses nucleotides - building
blocks of DNA - from the cell cytoplasm to make
this process possible.
• Drugs called reverse transcriptase inhibitors
block HIV's reverse transcriptase from using
these nucleotides.
• Nucleoside and nucleotide analog reverse
transcriptase inhibitors (NRTIs) - such as Zerit,
Epivir, and Viread - contain faulty imitations of the
nucleotides found in a T-cell's cytoplasm.
– Instead of incorporating a nucleotide into the
growing chain of DNA, the imitation building blocks
in NRTIs are inserted, which prevents the double
strand of DNA from becoming fully formed.
– Non-nucleoside reverse transcriptase inhibitors
(NNRTIs) - such as Viramune and Sustiva - block
reverse transcription by attaching to the enzyme in
a way that prevents it from functioning
 Drugs acting during viral synthesis
• Reverse transcription
– One way of doing this is to develop nucleotide or
nucleoside analogues that look like the building
blocks of RNA or DNA, but deactivate the enzymes
that synthesize the RNA or DNA once the analogue
is incorporated.
– This approach is more commonly associated with
the inhibition of reverse transcriptase (RNA to
DNA) than with "normal" transcriptase (DNA to
RNA).
– The first successful antiviral, acyclovir, is a
nucleoside analogue, and is effective against
herpesvirus infections.
– The first antiviral drug to be approved for treating
HIV, zidovudine (AZT), is also a nucleoside
analogue.
• An improved knowledge of the action of reverse
transcriptase has led to better nucleoside
analogues to treat HIV infections.
• One of these drugs, lamivudine, has been
approved to treat hepatitis B, which uses reverse
transcriptase as part of its replication process.
Researchers have gone further and developed
inhibitors that do not look like nucleosides, but
can still block reverse transcriptase.
• Another target being considered for HIV antivirals
include RNase H - which is a component of
reverse transcriptase that splits the synthesized
DNA from the original viral RNA .
 Nucleoside reverse transcriptase
inhibitors
• Abacavir
• Didanosine
• Lamivudine
• Stavudine
• Zalcitabine
• Zidovudine
Nonnucleoside reverse transcriptase
inhibitors
• Delavirdine
• Efavirenz
• Nevirapine
• Tenofovir
Drugs acting during viral synthesis
• If HIV succeeds in translating its
instructions from RNA to DNA, HIV must
then insert its DNA (also called the
preintegration complex) into the cell's
DNA.
– This process is called integration.
– In most human cells cell's DNA is
stored, in the nucleus
– In order for integration to occur, the
newly translated DNA must be
transported across the nuclear
membrane into the nucleus
• Once the viral RNA has successfully
bridged the nuclear membrane and been
escorted to the nucleus, HIV uses an
enzyme called integrase to insert HIV's
double-stranded DNA into the cell's
existing DNA. Integrase
• Another target for drugs is integrase,
which splices the synthesized DNA into
the host cell genome.
• Drugs that inhibit the HIV
preintegration complex from traveling
to the nucleus - integrase inhibitors -
are currently in early clinical trials
Viral Latency and Protein Synthesis

• After successful integration of the viral DNA, the host

cell is now latently infected with HIV.
• This viral DNA is referred to as provirus.
• The HIV provirus now awaits activation.
• When the immune cell becomes activated, this latent
provirus awakens and instructs the cellular machinery
to produce the necessary components of HIV, like
plastic pieces of a model airplane.
– From the viral DNA, two strands of RNA are constructed
and transported out of the nucleus.
– One strand is translated into subunits of HIV such as
protease, reverse transcriptase, integrase, and structural
proteins.
– The other strand becomes the genetic material for the new
viruses.
– Compounds that inhibit or alter viral RNA have been
identified as potential antiviral agents.

Cleavage and Viral Assembly

• Once the various viral subunits have been produced
and processed, they must be separated for the final
assembly into new virus.
• This separation, or cleavage, is accomplished by the
viral protease enzyme
• Drugs called protease inhibitors - such as Kaletra,
Crixivan, and Viracept - bind to the protease enzyme
and prevent it from separating, or cleaving, the
subunits. 
• If cleavage is successfully completed, the HIV subunits
combine to make up the content of the new virons. In
the next step of the viral life cycle, the structural
subunits of HIV mesh with the cell's membrane and
begin to deform a section of the membrane.
• This allows the nucleocapsid to take shape and viral
RNA is wound tightly to fit inside the nucleocapsid.
• Researchers are looking at drugs called zinc finger
inhibitors, which interfere with the packaging of the
viral RNA into the nucleocapsid
• Rifampicin acts at the assembly phase
 Drugs acting during viral synthesis

• Translation / ribozymes
– Yet another antiviral technique inspired by genomics is a set of drugs based on ribozymes,
which are enzymes that will cut apart viral RNA or DNA at selected sites. In their natural
course, ribozymes are used as part of the viral manufacturing sequence, but these synthetic
ribozymes are designed to cut RNA and DNA at sites that will disable them.
– A ribozyme antiviral to deal with hepatitis C has been suggested, and ribozyme antivirals are
being developed to deal with HIV.An interesting variation of this idea is the use of
genetically modified cells that can produce custom-tailored ribozymes.
– This is part of a broader effort to create genetically modified cells that can be injected into a
host to attack pathogens by generating specialized proteins that block viral replication at
various phases of the viral life cycle.
• Protease inhibitors
– Some viruses include an enzyme known as a protease that cuts viral protein chains apart so
they can be assembled into their final configuration. HIV includes a protease, and so
considerable research has been performed to find "protease inhibitors" to attack HIV at that
phase of its life cycle.
– Protease inhibitors became available in the 1990s and have proven effective, though they
can have unusual side effects, for example causing fat to build up in unusual places.
– Improved protease inhibitors are now in development.
– Protease inhibitors have also been seen in nature.
• A protease inhibitor was isolated from the Shiitake mushroom (Lentinus edodes).
• The presence of this may explain the Shiitake mushrooms noted antiviral activity in vitro.
 Protease inhibitors
• Indinavir
• Ritonavir
• Saquinavir
• Nelfinavir
• Amprenavir
• Lopinavir
 Drugs acting during viral synthesis

• Translation / antisense
• Genomics has not only helped find targets for many antivirals, it has
provided the basis for an entirely new type of drug, based on "antisense"
molecules. These are segments of DNA or RNA that are designed as
complementary molecule to critical sections of viral genomes, and the
binding of these antisense segments to these target sections blocks the
operation of those genomes. A phosphorothioate antisense drug named
fomivirsen has been introduced, used to treat opportunistic eye infections in
AIDS patients caused by cytomegalovirus, and other antisense antivirals are
in development. An antisense structural type that has proven especially
valuable in research is morpholino antisense.
• Morpholino oligos have been used to experimentally suppress many viral
types:
• caliciviruses
• flaviviruses (including WNV)
• dengue
• HCV]
• coronaviruses
Drugs acting during viral synthesis

• Transcription
• Once a virus genome becomes
operational in a host cell, it then
generates messenger RNA
(mRNA) molecules that direct
the synthesis of viral proteins.
Production of mRNA is initiated
by proteins known as
transcription factors. Several
antivirals are now being
designed to block attachment of
transcription factors to viral
DNA.
 Budding

• The final step of the viral life cycle is called budding.

• In this process, the genetic material enclosed in the nucleocapsid merges
with the deformed cell membrane to form the new viral envelope.
• With its genetic material tucked away in its nucleocapsid and a new outer
coat made from the host cell's membrane, the newly formed HIV pinches
off and enters into circulation, ready to start the whole process again
• During HIV's life cycle, the T-cell, known as the host cell, is altered and
perhaps damaged, causing the death of the cell.
• Scientists are not sure exactly how the cell dies but have come up with a
number of scenarios.
– First, after the cell becomes infected with a virus or other pathogen,
internal signals may tell it to commit suicide. This is known as apoptosis
or programmed cell death - a self-destruct program intended to kill the
cell with the hopes of killing the virus as well.
– A second possible mechanism for the death of the cell is that, as
thousands of HIV particles bud or escape from the cell, they severely
damage the cell's membrane, resulting in the loss of the cell.
– Another possible cause for the cell's death is that other cells of the
immune system, known as killer cells, recognize that the cell is infected
and inject it with chemicals that destroy it. 
• Whatever the mechanism of the cell's death, there is one less T-cell in
the body, and with this happening on a monumental scale, T-cells begin
to decline.
– Over time, there are not enough T-cells to defend the body.
– At this stage, a person is said to have acquired immunodeficiency
syndrome, or AIDS, and becomes susceptible to infections that a healthy
immune system could deal with.
– If this process of immune destruction is halted, a weakened immune
system may be able to repair some of the damage over time. 
• There is still much that is not known about HIV's life cycle.
– More research will enable scientists to coax HIV into giving up more
secrets of how it survives and spreads in the body.
– In turn, this will allow for the development of new drugs and vaccines
designed to stop it
• Two drugs named zanamivir (Relenza) and oseltamivir (Tamiflu) that
have been recently introduced to treat influenza prevent the release of
viral particles by blocking a molecule named neuraminidase that is found
on the surface of flu viruses, and also seems to be constant across a
wide range of flu strains
Schematic representation of
the HIV life cycle, depicting
the targets for anti-HIV
agents
• 19 compounds have been
licensed for use in HIV therapy.
• The five main drug categories
are
– Nucleoside reverse
transcriptase
inhibitors,
– Nucleotide reverse
transcriptase
inhibitors,
– Non-nucleoside
reverse transcriptase
inhibitors,
– Protease inhibitors
– Fusion inhibitors.
• New agents include viral
adsorption inhibitors and co-
receptor antagonists
 Immune system stimulation

• A second category of tactics for fighting viruses involves

encouraging the body's immune system to attack them, rather than
attacking them directly.
• Some antivirals of this sort do not focus on a specific pathogen,
instead stimulating the immune system to attack a range of
pathogens.
• One of the best-known of this class of drugs are interferons, which
inhibit viral synthesis in infected cells.
– One form of human interferon named "interferon alpha" is well-
established as part of the standard treatment for hepatitis B and C, and
other interferons are also being investigated as treatments for various
diseases.
• A more specific approach is to synthesize antibodies, protein
molecules that can bind to a pathogen and mark it for attack by
other elements of the immune system.
– Once researchers identify a particular target on the pathogen, they can
synthesize quantities of identical "monoclonal" antibodies to link up that
target.
– A monoclonal drug is now being sold to help fight
respiratory syncytial virus in babies,and antibodies purified from infected
individuals are also used as a treatment for hepatitis B
Acyclovir – mechanism of action

• In this HSV-infected human cell, the

acyclovir molecules enter the cell and are
converted to acyclovir monophosphate by
the HSV enzyme thymidine kinase (TK).
• Enzymes in the human cell add two more
phosphates to eventually form the active
drug acyclovir triphosphate.
• The acyclovir triphosphate competes with
2-deoxyguanosine triphosphate (dGTP)
as a substrate for viral DNA polymerase,
as well as acting as a chain terminator.
• In actual infection, the HSV releases its
naked capsid that delivers DNA to the
human nucleus
• The active drug acyclovir triphosphate
exerts its action on the viral DNA
located in the nucleus
Antiherpes Drugs
• Aciclovir
• Ganciclovir
• Cidofovir
• Foscarnet
• Vidarabine
• Idoxuridine
• Trifluridine
• Fomivirsen
 Aciclovir

• Cyclovir
• Herpex
• Acivir
• Acivirax
• Zovirax
• Zovir
 Aciclovir
• Aciclovir is active against most known
species in the herpesvirus family.
• In descending order of activity:
– Herpes simplex virus type I (HSV-1)
– Herpes simplex virus type II (HSV-2)
– Varicella zoster virus (VZV)
– Epstein-Barr virus (EBV)
– Cytomegalovirus (CMV) – least activity
 Aciclovir - Pharmacokinetics
• Aciclovir is poorly water soluble and has poor oral bioavailability
(15–30%), hence intravenous administration is necessary if
high concentrations are required.
• When orally administered, peak plasma concentration occurs
after 1–2 hours.
• Aciclovir has a high distribution rate
• Protein binding is reported to range from 9 to 33
• The elimination half-life of aciclovir is approximately 3 hours.
• It is renally excreted, partly by glomerular filtration and partly by
tubular secretion.
• The poor oral bioavailability may also be improved by
administering valaciclovir, which has an oral bioavailability of
about 55%.
• Valaciclovir is then converted to aciclovir by esterases via
 Aciclovir -Dosage forms

• Aciclovir is commonly marketed as

– Tablets (200 mg, 400 mg, 800 mg and 1 gram)

– Topical cream (5%)
• Cream preparations are used primarily for labial
herpes simplex.
– Intravenous injection (25 mg/mL)
• The intravenous injection is used when high
concentrations of aciclovir are required.
– Ophthalmic ointment (3%).
• The ophthalmic ointment preparation is only used
for herpes simplex keratitis.
 Aciclovir - Adverse effects
• Systemic therapy
– Common adverse drug reactions (≥1% of patients) associated with systemic
acyclovir therapy (oral or IV) include:
– nausea, vomiting, diarrhea and/or headache.
– In high doses, hallucinations have been reported.
– Infrequent adverse effects (0.1–1% of patients) include:
– agitation, vertigo, confusion, dizziness, oedema, arthralgia, sore throat,
constipation, abdominal pain, hair loss, rash and/or weakness.
– Rare adverse effects (<0.1% of patients) include:
– coma, seizures, neutropenia, leukopenia, crystalluria, anorexia
, fatigue, hepatitis, Stevens–Johnson syndrome,
toxic epidermal necrolysis and/or anaphylaxis.
• Additional common adverse effects, when acyclovir is administered IV,
include encephalopathy (1% of patients) and injection site reactions.
• The injection formulation is alkaline (pH 11), and extravasation may cause
local tissue pain and irritation.
• Renal impairment has been reported when acyclovir is given in large, fast
doses intravenously, due to the crystallisation of acyclovir in the kidneys.
 Aciclovir - Adverse effects

• Topical therapy
• Acyclovir topical cream is commonly associated
(≥1% of patients) with:
– dry or flaking skin or transient stinging/burning
sensations.
• Infrequent adverse effects include erythema or itch.
• When applied to the eye, acyclovir is commonly
associated (≥1% of patients) with transient mild
stinging.
• Infrequently (0.1–1% of patients), ophthalmic
aciclovir is associated with superficial
punctate keratitis or allergic reactions.
 Aciclovir -Toxicity

• The drug acts as a chromosome mutagen

• it should not be used during pregnancy unless the potential
benefit justifies the potential risk to the foetus
• However, it has not been shown to have any teratogenic or
carcinogenic effects and is frequently prescribed for pregnant
women, to prevent transmission of HSV to the neonate
• The acute toxicity (LD50) of acyclovir when given orally is greater than
1 g/kg, due to its low oral bioavailability
• Patients with renal impairment often exhibit elimination half-lives for
the drug that are five to six times longer than in those with normal
renal function, leading to accumulation of acyclovir in the plasma and
the likelihood of development of toxic reactions, such as lethargy,
confusion and myoclonus
• Cotard delusion has also been the result of adverse drug reactions to
acyclovir. The symptoms were associated with high serum
concentrations of CMMG, the principal metabolite of acyclovir.
 Anti-Influenza Agents
• Amantadine
• Rimantadine

• Oseltamivir (Tamiflu)
• Zanamivir (Relenza)
 Amantadine, Rimantadine
• Amantadine is no longer recommended for
treatment of influenza B infection.
• The mechanism of Amantadine's antiviral
activity involves interference with a viral
protein, M2 (an ion channel), which is
required for the viral particle to become
"uncoated" once taken inside a cell by
endocytosis.
 Amantadine, Rimantadine - Adverse
effects
• Amantadine has been associated with several
central nervous system (CNS) side effects, likely due to
amantadine's dopaminergic and adrenergic activity, and to a lesser
extent, its activity as an anticholinergic.
• CNS side effects include nervousness, anxiety, agitation, insomnia,
difficulty in concentrating, and exacerbations of pre-existing seizure
disorders and psychiatric symptoms in patients with schizophrenia
or Parkinson's disease.
• The usefulness of amantadine as an anti-parkinsonian drug is
somewhat limited by the need to screen patients for a history of
seizures and psychiatric symptoms.
• Rare cases of severe skin rashes such as
Stevens Johnson Syndrome and suicidal ideation in patients treated
with amantadine have also been reported
• Livedo reticularis is a possible side effect of amantadine use for
Parkinson's disease
 Oseltamivir
• Antiviral drug, slows the spread of influenza (flu) virus
between cells in the body by stopping the virus from
chemically cutting ties with its host cell
• Median time to symptom alleviation is reduced by 0.5–1
day.
• The drug is marketed under the trade name Tamiflu,
and is taken orally in capsules or as a suspension.
• It has been used to treat and prevent influenza A virus
and influenza B virus infection in over 50 million people
since 1999
• Oseltamivir is a prodrug, a (relatively) inactive chemical
which is converted into its active form by metabolic
process after it is taken into the body.
 Oseltamivir - Mechanism of action

• The prodrug oseltamivir is itself not virally effective;

– however, once in the liver, it is converted by natural
chemical processes, hydrolysed hepatically to its
active metabolite, the free carboxylate of oseltamivir
(GS4071).
• Oseltamivir is a neuraminidase inhibitor, serving as a
competitive inhibitor towards sialic acid, found on the
surface proteins of normal host cells.
• By blocking the activity of the viral neuraminidase (NA)
enzyme, oseltamivir prevents new viral particles from
being released by infected cells
 Oseltamivir - Indications and dosage

• Oseltamivir is indicated for the treatment and prevention of

infections due to influenza A and B viruses
• Tamiflu,
– as capsules (containing oseltamivir phosphate 98.5 mg equivalent to oseltamivir
75 mg)
– as a powder for oral suspension (oseltamivir phosphate equivalent to oseltamivir
6 mg/ml).
• Standard prophylactic dosage is 75 mg once daily for patients aged
13 and older, which has been shown to be safe and effective for up
to six weeks
 Oseltamivir - Possible side effects

• Common adverse drug reactions (ADRs)

associated with oseltamivir therapy
(occurring in over 1 percent of clinical trial
participants) include: nausea, vomiting,
diarrhea, abdominal pain, and
headache.
• Rare ADRs include: hepatitis and elevated
liver enzymes, rash, allergic reactions
including anaphylaxis, and Stevens–
Johnson syndrome.
Zanamivir (Relenza) - Dosing and side
effects

• The bioavailability of zanamivir is 2%.

• After inhalation, zanamivir is concentrated in the lungs
and oropharynx, where up to 15% of the dose is
absorbed and excreted in urine.
• Dosing is limited to the inhaled route.
– This restricts its usage, as treating asthmatics or
chronic obstructive pulmonary disease could induce
bronchospasms
• Zanamivir has not been known to cause toxic effects,
does not spread around through the body's systemic
circulation and shows no signs of viral resistance from
any flu
 Drugs Used in Viral Hepatitis
• Interferon alfa
• Adefovir
• Lamivudine
• Ribavirin