m m

6


? Antiviral drugs are a class of medication used specifically
to treat viral infections.
? Like antibiotics for bacteria, specific antiviral are used for
specific viruses.
? Unlike antibiotics, antiviral drugs do not destroy their
target pathogen; instead they inhibit their development.
? 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.
V 
 
’ize and shape:
? Àrom 20-300 nm
? Have typical shapes that aid in identification
Genome:
? Contain DNA or RNA
? Nucleic acids are the main component of the virus core
and are associated with core proteins.
? May be single stranded or double stranded circular or
linear
Capside:
? It is the protein coat enclosing the genome and core
proteins and consisting of capsomeres.
Envelope:
? Lipid bilayer membrane surrounding the capsid of some
viruses.
? It carries glycoproteins.
Virion:
? The complete infectious virus parts.
Viruses are obligate intracellular parasites and thus can
only replicate in living cells. ’ince viruses are strict
intracellular parasites, it depends on host metabolism.
And so it has no self metabolism, it has no specific
target.
 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.
Antiviral drugs types (approaches by life cycle stage):
 
6




 

Ex. Arildone

  

 

Ex. Amantadine, rimantadine.

  
 

An approach to target the processes that synthesize
virus components after a virus invades a cell.
Ex. acyclovir, gancicilovir, ribavirin.
 m 
 
 




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).
Ex. zidovudine, lamivudine
   
 Ex. fomivirsen
 6 Ex. Rifampicin
 
? Ex zanamivir (Relenza) and oseltamivir (Tamiflu)
! " 

 

Ex. interferons
 6




 

6 
It is very expensive, and is partly trial and error; it can be a
relatively slow process until an adequate molecule is
produced.
Mechanism of action:
Block attachment molecule on host cell or pathogen
indication
Against Picornaviruses, polioviruses, cold viruses
 " 
 


6
    
 

Amantadine is sold under the name #$
# for use

both as an antiviral and an antiparkinsonian drug.
Rimantadine is sold under the trade name %   and
is orally administered.
Mechanism of action
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.

Uses
? prophylactic agent against Asian influenza
? for the treatment of Influenzavirus A in adults
’ide effects
? CN’ side effects include nervousness, anxiety, agitation,
insomnia, difficulty in concentrating.
? Another potential side effect is livedo reticularis, a
dermatological reaction that results in skin mottling and
purpurish mesh network of blood vessels.

Resistance
? as a result of an amino acid substitutions at certain
locations in the transmembrane region of M2. This
prevents binding of the antiviral to the channel.
 " 
 

" 66&'

acyclovir (chemical name acycloguanosine, abbreviated as

ACV, is a guanosine analogue antiviral drug, marketed
under trade names such as J
,  
, 
,


, and 
.
Mechanism of action
? Acyclovir is selectively converted into acyclo-guanosine
monophosphate (acyclo-GMP) by viral thymidine kinase,
which is far more effective (3000 times) in phosphorylation
than cellular thymidine kinase. ’ubsequently, the
9   form is further phosphorylated into the
active    form, acyclo-guanosine triphosphate
(acyclo-GTP), by cellular kinases.
? Acyclo-GTP is a very potent inhibitor of viral DNA
polymerase; it has approximately 100 times greater affinity
for viral than cellular polymerase.

? As a substrate, acyclo-GTP is incorporated into viral DNA,

resulting in chain termination. It has also been shown that
viral enzymes cannot remove acyclo-GTP from the chain,
which results in inhibition of further activity of DNA
polymerase.
Microbiology:
Acyclovir is active against most species in the herpes
virus family;
? Herpes simplex virus type I (H’V-1)
? Herpes simplex virus type II (H’V-2)
? Varicella zoster virus (VZV)
? Epstein-Barr virus (EBV)
? Cytomegalovirus (CMV) -- least activity
Indications
Acyclovir is indicated for the treatment of H’V and VZV
infections, including:
? Genital herpes simplex (treatment and prophylaxis)
? Herpes simplex labialis (cold sores)
? Herpes zoster (shingles)
? Acute chickenpox in immunocompromised patients
? Herpes simplex encephalitis
? Acute mucocutaneous H’V infections in immunocompromised
patients
? Herpes simplex keratitis (ocular herpes)
? Herpes simplex blepharitis (not to be mistaken with ocular
herpes).
Adverse effects
’ystemic therapy
? Nausea, vomiting, diarrhea and/or headache.
? Encephalopathy when acyclovir is administered IV.
? Renal impairment has been reported when acyclovir
is given in large, fast doses intravenously, due to the
crystallisation of acyclovir in the kidneys.

Topical therapy
? Acyclovir topical cream is commonly associated
with: dry or flaking skin or transient stinging/burning
sensations.
? Infrequent adverse effects include erythema or itch.
"" ( 

? Ganciclovir is an antiviral medication used to treat or

prevent cytomegalovirus (CMV) infections.
? Ganciclovir sodium is marketed under the trade names
Cytovene and Cymevene (Roche).
? Ganciclovir for ocular use is marketed under the trade
name Vitrasert (Bausch & Lomb).
Mechanism of action
Ganciclovir is a synthetic analogue of 2'-deoxy-guanosine.
It is first phosphorylated to a deoxyguanosine
triphosphate (dGTP) analogue. This competitively inhibits
the incorporation of dGTP by viral DNA polymerase,
resulting in the termination of elongation of viral DNA.
Indications
Ganciclovir is indicated for:
? ’ight-threatening CMV retinitis in severely
immunocompromised people.
? CMV pneumonitis in bone marrow transplant recipients.
? Prevention of CMV disease in bone marrow and solid
organ transplant recipients.
? Confirmed CMV retinitis in people with AID’ .
Adverse effects

? Ganciclovir is commonly associated with a range of

serious haematological adverse effect include: anaemia,
thrombocytopenia.

? fever, nausea, vomiting, dyspepsia, diarrhoea, abdominal

pain, flatulence, anorexia, raised liver enzymes, headache,
confusion, hallucination, seizures, pain and phlebitis at
injection site (due to high pH), sweating, rash, itch,
increased serum creatinine and blood urea
concentrations.
""" 
')

Ribavirin is a prodrug, which when metabolised resembles

purine RNA nucleotides. In this form it interferes with RNA
metabolism required for viral replication.
 Uses
? Ribavirin is active against a number of DNA and RNA
viruses. It is a member of the nucleoside antimetabolite
drugs that interfere with duplication of viral genetic
material.

? Ribavirin is remarkable as a small molecule for its wide

range of activity, including important activities against
influenzas, flaviviruses and agents of many viral
hemorrhagic fevers.
 Adverse effects

? The primary observed serious adverse side-effect of

ribavirin is hemolytic anemia, which may worsen
preexisting cardiac disease.
m 6



? Antiretroviral drugs are medications for the treatment of
infection by retroviruses, primarily HIV.

? Most viruses have DNA or RNA. Reteroviruses on the

other hands are intermediate class that has RNA which
converts to DNA during replication by reverse
transcriptase enzyme.

? There are different classes of antiretroviral drugs that act

at different stages of the HIV life-cycle.
&  

? Antiretroviral drugs are broadly classified by the phase of

the retrovirus life-cycle that the drug inhibits.
a. Nucleoside and nucleotide reverse transcriptase inhibitors
(nRTI) inhibit reverse transcription by being incorporated
into the newly synthesized viral DNA and preventing its
further elongation.
b. Non-nucleoside reverse transcriptase inhibitors (NNRTI)
inhibit reverse transcriptase directly by binding to the
enzyme and interfering with its function.
c. Protease inhibitors (PIs) target viral assembly by inhibiting
the activity of protease, an enzyme used by HIV to cleave
nascent proteins for final assembly of new virons.
1a.Nucleoside analog reverse transcriptase
inhibitors.

"
  

? Zidovudine or azidothymidine (AZT) was the first approved

treatment for HIV. It is sold under the name Retrovir.

? In order to be incorporated into the viral DNA, NRTIs must be

activated in the cell by the addition of three phosphate groups to
their deoxyribose moiety, to form NRTI triphosphates. This
phosphorylation step is carried out by cellular kinase enzymes.
AZT use was a major breakthrough in AID’ therapy in
the 1990s that significantly altered the course of the
illness and helped destroy the notion of the 1980s
and early 90s that HIV/AID’ was an instant death
sentence.
Indications

? AZT may be used in combination with other antiretroviral

medications to substantially reduce the risk of HIV
infection following a significant exposure to the virus.

? AZT is also recommended as part of a regimen to prevent

mother-to-child transmission of HIV during pregnancy,
labor, and delivery.
 ’ide effects
? Common side effects of AZT include nausea, headache,
changes in body fat, and discoloration of fingernails and
toenails. More severe side effects include anemia and
bone marrow suppression

Viral resistance
? AZT does not destroy the HIV infection, but only delays
the progression of the disease and the replication of
virus, even at very high doses. During prolonged AZT
treatment, HIV has the ability to gain an increased
resistance to AZT by mutation of its reverse
transcriptase.
 Mode of action
? Like other reverse transcriptase inhibitors, AZT works by
inhibiting the action of reverse transcriptase, the enzyme
that HIV uses to make a DNA copy of its RNA.

? Reverse transcription is necessary for production of the

viral double-stranded DNA, which is subsequently
integrated into the genetic material of the infected cell
(where it is called a provirus).

? AZT has a 100-fold greater affinity for the HIV reverse

transcriptase than for the human DNA polymerase alpha,
accounting for its selective antiviral activity.
 ""   
Zeffix, Heptovir, Epivir

cytidine

Lamivudine has been used for treatment of chronic

hepatitis B at a lower dose than for treatment of HIV.
 Mechanism of action

? Lamivudine is an analogue of cytidine. It can inhibit both

types (1 and 2) of HIV reverse transcriptase and also the
reverse transcriptase of hepatitis B.

Resistance
? mutation in amino acid sequence.
 """   

Didanosine (DDI) Videx and Videx EC.

? It is a reverse transcriptase inhibitor, effective
against HIV and used in combination with other
antiretroviral drug therapy as part of highly active
antiretroviral therapy (HAART).
 Mechanism of action

? Didanosine (ddI) is a nucleoside analogue of adenosine. It

differs from other nucleoside analogues, because it does
not have any of the regular bases, instead it has
hypoxanthine attached to the sugar ring.

? Within the cell, ddI is phosphorylated to the active

metabolite of dideoxyadenosine triphosphate, ddATP, by
cellular enzymes. Like other anti-HIV nucleoside analogs,
it acts as a chain terminator by incorporation and inhibits
viral reverse transcriptase by competing with natural
dATP.
 Adverse effects

? The most common adverse events with didanosine are

diarrhea, nausea, vomiting, abdominal pain, fever,
headache and rash.
 "'

 

cytidine
? Zalcitabine (ddC), also called dideoxycytidine, is a
nucleoside analog reverse transcriptase inhibitor
(NARTI) sold under the trade name Hivid.
 Mechanism of action

? Zalcitabine is a derivative of the naturally existing

deoxycytidine, made by replacing the hydroxyl group in
position 3' with a hydrogen.

? It is phosphorylated in T cells and other HIV target cells

into its active triphosphate form, ddCTP.
? This active metabolite works as a substrate for HIV
reverse transcriptase, and also by incorporation into the
viral DNA, hence terminating the chain elongation due to
the missing hydroxyl group. ’ince zalcitabine is a reverse
transcriptase inhibitor it possess activity only against
retroviruses.

Adverse effects
? nausea and headache.
? peripheral neuropathy, oral ulcers, oesophageal ulcers
and, rarely, pancreatitis.
 ' $
  

? ’tavudine (brand name Zerit) is a nucleoside analog

reverse transcriptase inhibitor (NARTI) active against
HIV.
Mechanism of action

? ’tavudine is an analog of thymidine. It is phosphorylated by

cellular kinases into active triphosphate. ’tavudine
triphosphate inhibits the HIV reverse transcriptase by
competing with natural substrate, thymidine triphosphate.
It also causes termination of DNA synthesis by incorporating
into it.

Adverse effects

The main severe adverse effect is peripheral neuropathy,

which can be corrected by reducing dosage.
1b. Nucleotide analog reverse transcriptase
inhibitors (NtARTIs or NtRTIs)

? Normally, nucleoside analogs are converted into

nucleotide analogs by the body.
? Taking nucleotide analog reverse transcriptase inhibitors
directly allows conversion steps to be skipped.
"  
Viread

Indications
? Tenofovir is indicated in combination with other antiretroviral
agents for the treatment of HIV-1 infection in adults
Adverse effects
? include nausea, vomiting, diarrhea, and asthenia
? Tenofovir has also been implicated in causing renal toxicity,
particularly at elevated doses
2. Non-nucleoside reverse transcriptase
inhibitors (NNRTIs)
I. Efavirenz

? Efavirenz (brand names ’ustiva and ’tocrin) is used as part of

highly active antiretroviral therapy (HAART) for the treatment
of a human immunodeficiency virus (HIV) type 1.

? Efavirenz is also used in combination with other antiretroviral

agents as part of an expanded postexposure prophylaxis
regimen to prevent HIV transmission for high risk groups.
Mechanism of action
? Efavirenz falls in the NNRTI class of antiretrovirals. Both
nucleoside and non-nucleoside RTIs inhibit the same target, the
reverse transcriptase enzyme, an essential viral enzyme which
transcribes viral RNA into DNA. Unlike nucleoside RTIs, which
bind at the enzyme's active site, NNRTIs bind within a pocket
termed the NNRTI pocket.

Adverse effects
? Psychiatric symptoms, including insomnia, confusion, memory
loss, and depression, are common.
? More serious symptoms such as psychosis may occur in patients
with compromised liver or kidney function.
? Rash, nausea, dizziness and headache may occur
 ""   

? Nevirapine, (Viramune) is a non-nucleoside reverse

transcriptase inhibitor (NNRTI) used to treat HIV-1
infection and AID’.
? As with other antiretroviral drugs, HIV rapidly develops
resistance if nevirapine is used alone, so recommended
therapy consists of combinations of three or more
antiretrovirals.
Mode of action
? Nevirapine falls in the non-nucleoside reverse transcriptase
inhibitor (NNRTI) class of antiretrovirals. Both nucleoside
and non-nucleoside RTIs inhibit the same target, the reverse
transcriptase enzyme.

Adverse effects
? The most common adverse effect of nevirapine is the
development of mild or moderate rash .
? Nevirapine may cause severe or life-threatening liver
toxicity, usually emerging in the first six weeks of treatment.
 """  

? Delavirdine (DLV) is used as part of highly active

antiretroviral therapy (HAART) for the treatment of
human immunodeficiency virus (HIV) type 1.
3. Protease inhibitor
? Protease inhibitors (PIs) are a class of medications used to
treat or prevent infection by viruses, including HIV and
Hepatitis C.

? PIs prevent viral replication by inhibiting the activity of

HIV-1 protease, an enzyme used by the viruses to cleave
nascent proteins for final assembly of new virons.

? Protease inhibitors were the second class of antiretroviral

drugs developed.
 " $*  

? ’aquinavir (Invirase and Àortovase-) is An

antiretroviral drug used in HIV therapy.
Mode of action

? ’aquinavir is a protease inhibitor. Proteases are enzymes that

cleave protein molecules into smaller fragments. HIV protease is
vital for both viral replication within the cell and release of
mature viral particles from an infected cell. ’aquinavir inhibits
both HIV-1 and HIV-2 proteases.

Adverse reactions

? Mild gastrointestinal symptoms, including diarrhea, nausea,

loose stools & abdominal discomfort.
 "" "  

? Indinavir (IDV; trade name Crixivan) is a protease inhibitor used

as a component of highly active antiretroviral therapy (HAART) to
treat HIV infection and AID’.

’ide effects
? Kidney stones
? Metabolic abnormalities including hyperlipidemia (cholesterol or
triglyceride elevations)
? alterations in body shape known as lipodystrophy
 """ 
 

? Ritonavir (Norvir)is an antiretroviral drug from the protease

inhibitor class used to treat HIV infection and AID’.

? Ritonavir is frequently prescribed with HAART, not for its

antiviral action, but as it inhibits the same host enzyme that
metabolizes other protease inhibitors. This inhibition leads
to higher plasma concentrations of these latter drugs
Method of action
? Ritonavir is used to inhibit a particular liver enzyme that
normally metabolizes protease inhibitors, cytochrome P450-
3A4 .

’ide effects
? diarrhea
? nausea and vomiting
? abdominal pain
? dizziness
? insomnia
? sweating
? taste abnormality
? metabolic hypercholesterolemia and hypertriglyceridemia
 "'    (Kaletra)
? It represent a co-formulation with a sub-therapeutic dose
of Ritonavir, as a component of combination therapy to
treat AID’.

Adverse effects
? The most common adverse effects observed with
lopinavir/ritonavir are diarrhea and nausea.
? Abdominal pain, asthenia, headache, vomiting and,
particularly in children, rash.
? Raised liver enzymes and hyperlipidemia (both
hypertriglyceridemia and hypercholesterolemia) are also
commonly observed during lopinavir/ritonavir treatment.
   

%
(Vitravene)
? It is used in the treatment of cytomegalovirus retinitis (CMV)
in immunocompromised patients, including those with AID’.

Mechanism
? It is an oligonucleotide that blocks translation of viral mRNA by
binding to a coding segment of a key CMV gene.

Administration
? It is available as an intraocular injection.
 6

 

? Rifampicin or rifampin is a bactericidal antibiotic drug of

the rifamycin group.

? Rifampicin has some effectiveness against vaccinia virus.

  
+


? [seltamivir is an antiviral drug that slows the spread of influenza

(flu) virus between cells in the body by stopping the new virus from
chemically cutting ties with its host cell.

? [seltamivir was the first  
 neuraminidase inhibitor

commercially available

? The drug is sold under the trade name Tamiflu and is taken orally in
capsules or a drink.
? It has been used to treat and prevent Influenzavirus A and
Influenzavirus B.

? [seltamivir becomes active in the body once it passes

through the liver.

? '    is an enzyme on the surface of

influenza viruses that enables the virus to be released from
the host cell.

? Drugs that inhibit neuraminidase, known as neuraminidase

inhibitors, are used to treat influenza.
? When influenza virus reproduces, it attaches to the cell
surface using hemagglutinin, a molecule found on the
surface of the virus which binds to sialic acid groups.

? ’ialic acids are found on various glycoproteins at the host

cell surface, and the virus exploits these groups to bind the
host cell.

? In order for the virus to be released from the cell,

neuraminidase must enzymatically cleave the sialic acid
groups from host glycoproteins.
Mode of action
? [seltamivir 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 neuraminidase, [seltamivir prevents
new viral particles from being released by infected
cells.
Indications
? [seltamivir is indicated for the treatment and prevention
of infections due to influenza A and B virus in people at
least one year of age.

? [seltamivir may be given as a preventive measure either

during a community outbreak or following close contact
with an infected individual.

Adverse effects
? nausea, vomiting, diarrhea, abdominal pain, and
headache.
? Rare : hepatitis and elevated liver enzymes, rash, allergic
reactions.
Resistance
? Mainly mutations to neuraminidase gene.

? As with other antivirals, resistance to the agent was

expected with widespread use of oseltamivir, though the
emergence of resistant viruses was expected to be less
frequent than with amantadine or rimantadine.

 

? Zanamivir is a neuraminidase inhibitor used in the

treatment and prophylaxis of Influenzavirus A and
Influenzavirus B.
? It was the first neuraminidase inhibitor commercially
developed.
? It is currently marketed by Glaxo’mithKline under the
trade name Relenza.
? According to the CDC, no flu, seasonal or pandemic
has shown any signs of resistance to Zanamivir
Indications
? In the treatment of infections caused by Influenzavirus
A and Influenzavirus B.

Adverse effects
? Zanamivir is specific to the influenza virus, has not
been known to cause toxic effects, and does not
spread around through the body's systemic circulation.
? It also shows no signs of viral resistance. However, due
to a lack of reports or evidence about its toxicity, the
ÀDA does not license it for use in children under 7
years of age.
! " 

 

"

? Interferons (IÀNs) are natural cell-signaling proteins
produced by the cells of the immune system of most
vertebrates in response to challenges such as viruses,
parasites and tumor cells.

? They belong to the large class of glycoproteins known as

cytokines and are produced by a wide variety of cells in
response to the presence of double-stranded RNA, a key
indicator of viral infection.
Types of interferon
Based on the type of receptor through which they signal,
human interferons have been classified into two major
types.
? Interferon type I: All type I IÀNs bind to a specific cell
surface receptor complex known as the IÀN-ɲ receptors.
The type I interferons present in humans are IÀN-ɲ, IÀN-ɴ
and IÀN-ʘ.
? Interferon type II: In humans this is IÀN-ɶ.

? All classes are very important in fighting viral infections.

? Their presence also accounts for some of the host
symptoms to infections, such as sore muscles and fever.
Àunction
? Interferons assist the immune response by
1. Inhibiting viral replication within host cells
2. Activating natural killer cells and macrophages
3. Increasing the resistance of host cells to viral infection.

? As an infected cell dies from the cytolytic virus, thousands

of viruses will infect nearby cells. However, the infected cell
releases interferon and warns these other cells of the
presence of the virus. These neighboring cells, in response,
produce large amounts of an enzyme known as protein
kinase R (PKR).
? If a virus infects a cell that has been ͞pre-warned͟ by
interferon, the PKR begins transferring phosphate groups
(phosphorylating) to a protein known as eIÀ-2, an
eukaryotic translation initiation factor, which forms an
inactive complex with another protein called eIÀ2B to
reduce translation initiation and protein synthesis.

? This prevents both viral replication and normal cell

ribosome function, potentially killing both the virus and
susceptible host cells.

? Àollowing PKR activation, another cellular enzyme, RNAse L

is also induced. This enzyme destroys all RNA within the
cells thereby further reducing protein synthesis of both viral
and host genes.
Virus resistance to interferons

? Many viruses have evolved mechanisms to resist interferon

activity. They circumvent the IÀN response by
1. blocking signaling events,
2. preventing further IÀN production
3. inhibiting the functions of proteins that are induced by
IÀN.
Notice
? Interferons are host specific but not virus specific.
Diseases
? The immune effects of interferons have been exploited to
treat several diseases.
? Agents that activate the immune system, such as small
imidazoquinoline molecules can induce IÀN-ɲ.
? ’ynthetic IÀNs are also made, and administered as
antiviral, antiseptic and anticarcinogenic drugs, and to
treat some autoimmune diseases.
? Interferon therapy is used (in combination with
chemotherapy and radiation) as a treatment for many
cancers.
? Both hepatitis B and hepatitis C are treated with IÀN-ɲ,
often in combination with other antiviral drugs.
Adverse effects
? The most frequent adverse effects are flu-like symptoms:
increased body temperature, feeling ill, fatigue, headache,
muscle pain, convulsion, dizziness, hair thinning, and
depression.

Recombinant ɲ-interferon
? Very expensive
? Gene of ɲ-interferon is cut and incorporated in bacteria or
yeast and multicopies are produced from it.