Antiviral and Anti-HIV

Drugs
 Antiviral Agents
 Antiviral agents are drugs that cure or control virus
infections.
 Unlike antibacterial drugs, which may cover a wide range
of pathogens, antiviral agents tend to be narrow in
spectrum, and have limited efficacy
 The reason for this is the fact that viruses are obligate
intracellular parasites which use the host cell for synthesizing
viral proteins and for replication; accordingly any drug that
interferes significantly with viral replication is likely to be toxic
to the host
 As a class, the antiviral drugs are not curative, and must
be used either prophylactically or early in the
development of an infection
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 Strategies for Antiviral Therapy

 Any stage of viral replication can be a target for

antiviral drugs

The only requirements are:

The stage targeted is essential for virus replication
The therapeutic agent is active against the virus
while having "acceptable toxicity" to the host
organism

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Stages in Virus Replication which are Possible
Targets for Chemotherapeutic Agents
 Attachment to host cell
 Uncoating - (Amantadine)
 Replication of viral RNA or DNA - (Nucleoside analogues)
 Synthesis of viral mRNA - (Interferon)
 Translation of mRNA - (Interferon)
 Maturation of new virus proteins (Protease inhibitors)
 Budding, Release.

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Classification of Antivirals

Antivirals effective against influenza virus

Antivirals effective against herpes virus

Antivirals effective against respiratory syncytial

virus

Antivirals effective against hepatitis C and B

Antivirals effective against HIV virus

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 1. Antiviral Agents Effective Against
Influenza Viruses
A. Agents Effective Against Influenza Virus Type A

Adamentane Derivatives

i. Amantadine HCl

ii. Rimantadine HCl H3C NH2 .HCl

NH2.HCl

1-Adamantanamine -Methyl-adamantanemethylamine
Hydrochloride hydrochloride 6
 The clinical usefulness of amantadine and rimantadine is
limited to the prevention and treatment of influenza A virus
infections
 When they are taken orally, 24-48 hours after the onset of
illness, they reduce the duration of fever and other symptoms
by preventing invasion of additional cells
 Amantadine is excreted by the kidneys unchanged via
glomerular filtration and tubular secretion while rimantadine is
metabolized by the liver (75%) and is also excreted by the
kidneys
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 Both amantadine and rimantadine can cause central

nervous system (CNS) and gastrointestinal side effects.

 However, the incidence of CNS side effects (e.g.,

nervousness, anxiety, disorientation, and insomnia...) is

higher among persons taking amantadine than among

those taking rimantadine

 Rimantadine also has a longer duration of action
Mechanism of Action
 The two drugs inhibit the early stages of viral replication,
blocking the uncoating of the viral genome and the
transfer of nucleic acid into the host cells
 Amantadine inhibits also virus particle penetration into
the host cells

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B) Agents Effective Against Virus Influenza Types A and B
Neuraminidase Inhibitors (Sialic Acid Analogs)

Zanamivir Oseltamivir

HO OH
H
HO O O COOC2H5
H3CCONH COOH 3
4
5
HN HN
NH2 NH2 . H3PO4
N O
H
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 The neuraminidase inhibitors, zanamivir and oseltamivir,
are chemically related drugs that have activity against both
influenza A and B viruses
 Zanamivir is an orally inhaled powdered drug that is
approved for treatment of influenza in persons aged 7
years and older
 Zanamivir is not approved for chemoprophylaxis of
influenza

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 Oseltamivir is an orally administered capsule or oral
suspension that is approved for treatment of influenza in
persons aged 1 year and older. Oseltamivir is also approved
for chemoprophylaxis of influenza in persons aged 13 years
and older.
 Oseltamivir is an ethyl ester prodrug requiring ester
hydrolysis for conversion to the active form, oseltamivir
carboxylate
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Mechanism of Action
 Influenza viruses are surrounded by a protein coat and a lipid
envelope
 In the lipid membrane there are two surface glycoproteins
 Hemaglutinin (HA) is an enzyme important for binding viruses to target cell
receptor via a terminal sialic acid residue
 Neuraminidase (NA) an enzyme involved in various activation of influenza
viruses
 NA is found in both influenza A and B and is thought to be involved in
catalytically cleaving glycosidic bonds between terminal sialic acid
and an adjacent sugar
 The cleavage of sialic acid bonds facilitates the spread of viruses and
as a result increases the infectiveness or pathogen city of the virus.
 NA inhibitors interfere with the spread of the infection by blocking
sialic acid bonds cleavage
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2. Antiviral Agents Effective Against
Herpes Virus
 The family of herpes virus includes:
A. Herpes simplex types 1 and 2 (HSV1, HSV2),
Varicella Zoster (VZV) and Epstein Bar (EBV)
B. Cytomegalovirus (CMV)
A) Agents Effective Against HSV1 and 2, VZV and EBV
 Drugs in this class are Nucleotide analogues with sugar
modification. They resemble natural nucleotides, but have
an incomplete ribose group. They act as DNA polymerase
inhibitors.

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Acyclovir Valacyclovir HCl
O
O
N
HN HN
N

H2N N H2N N N NH2 . HCl

N
O CH(CH3)2
OH O
O H
O

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 Acyclovir is a synthetic analog of the normal metabolite
2’-Deoxyguanosine.
 Acyclovir is most active against HSV but also has activity
against VZV with little activity against EBV and no activity
against CMV
 Valacyclovir is a valine ester of acyclovir that is well
absorbed. Its bioavailability is 2-5 greater than acyclovir.
So lower dose is possible, at less frequent intervals. It is
used for the treatment and suppression of genital herpes
infection.

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Famiciclovir

O O

N HN N
HN 1. Esterase
2. Oxidase N
H2 N N N H2 N N
CH3 -CO-O HO

CH3 -CO-O HO

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 Famiciclovir is the prodrug of penciclovir which is the
active form and a guanosine analog
 It has a very high bioavailability of 77%. It is converted into
penciclovir by a two step process
 The first step occurs in the gut and the second step in the
liver and it has a long half life in the gut than acyclovir
 It acts as an inhibitor of viral DNA polymerase and also as a
chain terminator
 At present famiciclovir is licensed for the treatment of
shingles and also used for the treatment and suppression
of genital herpes

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Mechanism of Action

 They are phosphorylated to the monophosphate by viral

thymidine kinase and then to the di- then triphosphate by a
host cell kinase.
 The triphosphate form of the drug blocks DNA replication
of viral DNA by competitive inhibition of viral DNA
polymerase and incorporation and termination of the
growing viral DNA chain. Chain termination occurs because
the drug triphosphate lacks the 3-hydroxy group of cyclic
sugar 19
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Selectivity of Action

 These drugs reduce DNA synthesis in virus-infected cells

without affecting the active replication of uninfected cells
because:
 Viral thymidine kinase phosphorylates the drug over

100 times faster than host cells

 Acyclovir triphosphate competitively inhibits viral
DNA polymerases, and to a much smaller extent
cellular DNA polymerases 21
 Other Drugs Used as Topical Applications
for Herpes

1. Tifluridine 2. Idoxuridine
 These are pyrimidine analogs with base modification.
Because of their mutagenic and teratogenic effects
following systemic administration, idoxuridine and
trifluridine are only suitable for topical use.

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Tifluridine Idoxuridine
)R = I(
)R = CF3(
O
R
HN

O N
O
HO

HO
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 B) Agents Effective Against Cytomegalovirus
(CMV)
i. Ganciclovir
 Ganciclovir is a deoxyguanosine analog that differs from
acyclovir in having an additional hydroxymethyl group on
the acyclic side chain.
 It is the preferred drug for treating (CMV) infections in
patients with acquired immune deficiency syndrome (AIDS)
or other immunodeficiencies.
 This agent has inhibitory activity against all herpes viruses
but its unique characteristic is the potent inhibition of CMV
replication.
 It has very poor oral bioavailability (3 percent), and,
therefore, mostly given intravenously. 24
Mechanism of Action
 It is an acyclic guanine nucleoside analog and is
activated to the nucleoside triphosphate that
incorporates into new viral DNA and inhibits DNA
polymerase
 CMV is deficient in thymidine kinase this is why
acyclovir has no activity against CMV

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ii. Foscarnet

 It is trisodium phosphonoformate

 It is the second drug used in the treatment of CMV

infections, particularly CMV retinitis, in
immunocompromised patients
 It is given intravenously, and it has proved effective in
delaying progression of CMV retinitis
O

P 3 Na
O COO
O 26
Mechanism of action
 It is an Inorganic pyrophosphate analog that works by
reversibly blocking the pyrophosphate binding site on viral
DNA polymerase, thereby terminating chain elongation.
 Unlike nucleoside analogs, foscarnet does not need to be
activated by cellular or viral kinases.

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3. Antiviral Agents Effective Against
Respiratory Syncytial Virus

Ribavirin
 Ribavirin is a synthetic triazole nucleoside in which both
the base and the D-ribose sugar are necessary for antiviral
activity
 Ribavirin is approved only for the treatment of respiratory
syncytial virus (RSV) infection in infants
O
H2N
N
N
N
O
HO

HO OH
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 Mechanism of action
 The antiviral mechanism of action of ribavirin is not fully
defined but relates to the ability of cells to take up ribavirin
and to form active triphosphate derivatives
 Intracellular phosphorylation to the mono-, di-, and
triphosphate derivatives is mediated by host cell enzymes
 Ribavirin monophosphate inhibits inosine monophosphate
dehydrogenase which is involved in the synthesis of
guanosine monophosphate and the triphosphate is an
inhibitor of viral RNA polymerase

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 4. Antiviral Agents Effective Against Hepatitis B
and C
Interferons
 Interferons are a family of cytokines discovered in the
late 1950s,with broad spectrum antiviral and potential
anticancer activity making them biologic response
modifiers (BRM)
 There are three main types of interferons; alpha, beta, and
gamma interferons which differ both structurally and
antigenically
 Alpha interferon is produced mainly by certain leukocytes,
beta interferon by epithelial cells and fibroblasts, and
gamma interferon by T and natural killer cells
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 Interferon consists of small proteins with molecular
weights ranging from 20,000 to 160,000
 Interferons are released from eukaryotic cell types in
response to virus infection and other biological inducers
 The important role played by interferons as a defense
mechanism is supported by three types of experimental
and clinical observations:-
For many viral infections, a strong correlation has been
established between interferon production and natural
recovery

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  Inhibition of interferon production or action
enhances the severity of infection
 Treatment with interferon protects against infection

 For many years the supply of human interferon for

research was limited by costly extraction techniques In
1980, however, the protein became available in greater
quantities through genetic engineering (recombinant
DNA technology)

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Mechanism of Action of Interferons

 Interferons act by direct inhibition of viral replication

 Interferons inhibit the transcription and translation of

mRNA into viral nucleic acid and protein
 Interferons may also act by blocking synthesis of a cleaving
enzyme required for viral release

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Interferon Inducers
 These are chemical compounds that induce the
production and release of interferon in humans

The most known interferon inducers are:

Statolon
-a double-stranded RNA produced in Penicillium
stoloniferum culture
Ampligen
-a polynucleotide derivative that was found to have in-vitro
anti-HIV activity and acts also as immunomodulator
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Clinical Application
 Recombinant alpha and beta interferons are now available
and have been used for the treatment of chronic hepatitis
C (plus ribavirin) and chronic hepatitis B
 Other uses of interferons include the treatment of
influenza, herpes zoster and genitalis, common cold
infections and cancers such as breast cancer and lung
carcinoma
Disadvantage of Interferon Treatment
 GIT problems
 CNS side effects
 Hypotension, anorexia and weight loss

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 5. Antiviral Agents Effective Against HIV

HIV target
 Several different kinds of cells have proteins on their
surface that are called CD4 receptors
 HIV searches for cells that have CD4 surface receptors,
because this particular protein enables the virus to bind to
the cell
 Although HIV infects a variety of cells, its main target is the
T4-lymphocyte (also called the "T-helper cell"), a kind of
white blood cell that has lots of CD4 receptors

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 The T4-cell is responsible for warning your immune system
that there are invaders in the system
 When the number of CD4 cells drops to a certain level
because of HIV infection, the body's immune system
weakens
 As a result, organisms such as fungi, viruses, and parasites
can cause serious infections in people with HIV
 When these infections occur, or when the number of CD4
cells drops below a certain level, a person with HIV
infection is said to have AIDS

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HIV Types
 Two types of HIV can be distinguished genetically and
antigenically
HIV-1 is the cause of the current pandemic/ having
widespread effect
HIV-2 is found in West Africa but rarely elsewhere
and causes AIDS much more slowly than HIV-1

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Classification of Anti Retroviral Agents

 Anti retroviral agents are classified into three

groups:-

1. Nucleoside analogs reverse transcriptase inhibitors

(NRTI)

2. Non-nucleoside analogs reverse transcriptase

inhibitors (NNRTI)

3. HIV Protease inhibitors

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 A) Nucleoside Analogs Reverse Transcriptase
Inhibitors (NRTI)
 The enzyme reverse transcriptase catalyzes the synthesis of
DNA from RNA by simultaneous binding of both the nucleotide
and RNA at its catalytic active site or
 Reverse transcriptase enzyme (RT) is one which reverses the
usual information flow in a cell to opposite order which means
that DNA is produced on an RNA template
 The synthesis of viral DNA under the direction of (RT) requires
availability of purines and pyrimidines nucleosides and
nucleotides
 Therefore the aim is to design drugs which mimic natural
nucleosides but with a variety of chemical modifications

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Zidovudine (AZT) Stavudine (D4T)

O O
CH3 CH3
HN HN

O N O N
O O
HO HO

N3

NH2 O

N N NH
O N N
O N
O
HO HO
S S

Lamivudine (3TC) Didanosine (DDI)

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 Zidovudine was the first antiviral agent shown to have
beneficial effect against HIV infection
 However, after prolonged use, AZT-resistant strains rapidly
appears which limits the effect of AZT
 Zidovudine is an analog of thymidine in which the azido
group is substituted at the 3 carbon atom of the
dideoxyribose moiety

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 Stavudine differs in structure from thymidine by
replacement of the 3’hydroxyl group with a hydrogen atom
and a double bond in the 2’and 3’ positions of deoxyribose
ring
 Lamivudine is an analog of 2’-deoxycytidine in which the
3’-methylene group of deoxyribose ring is replaced with a
sulfur atom
 Didanosine is a purine dideoxynucleoside which is an
analog of inosine
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Mechanism of Action

 They are first bioactivated to triphosphate by cellular

kinase. These phosphates act as:
Competitive inhibitor of viral reverse transcriptase.
 Chain terminators.

 They are incorporated into viral DNA and viral DNA

synthesis which is terminated because these drugs lack a
3’–OH group, consequently no more phosphodiester
bonds could be formed.
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 B. Non Nucleoside Analogues Reverse
Transcriptase Inhibitors (NNRTI)

 FDA has recently approved several NNRTI. They should not

be used as monotherapy but they are used with NRTI to
obtain synergistic activity in decreasing viral load and
increasing CD4+ cell counts.
 Unlike NRTIs, members of this class are highly specific to
HIV-1 RT without affecting the host DNA polymerases

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Nevirapine Efavirenz
H O
CH3
N F3C C C
Cl
O
N N N
N O
H

Delavirdine 46
 Mechanism of Action

 These drugs noncompetitively inhibit viral RT, presumably

by binding to a site other than the nucleoside and template
binding sites (allosteric site)
 This interaction between the NNRTI and the HIV-1 RT
produces a conformational change that results in the
inactivation of the viral RT

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 C. HIV Protease Inhibitors
What is the role of protease enzyme?
 HIV protease is a proteolytic enzyme responsible for cleaving
the large polyprotein precursor into biologically active protein
products
 When viral RNA is translated into a polypeptide sequence,
that sequence is assembled in a long chain that includes
several individual proteins (reverse transcriptase, protease,
integrase)
 Before these enzymes become functional, they must be cut from the
longer polypeptide chain
 Viral protease cuts the long chain into its individual enzyme
components which then facilitate the production of new viruses

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49
 Protease Inhibitors

 Inhibitors of this viral protease can be used to fight HIV

infection. By blocking the ability of protease to cleave the
viral polypeptide into functional enzymes, protease
inhibitors interfere with continued infection.
 Most current protease inhibitors are complex
peptidomimetic compounds with poor aqueous solubility,
low bioavailability and short plasma half-life.

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 The complexity of these agents not only contributes to
their high cost but also increases the potential for
unwanted drug interactions
 Four protease inhibitors, saquinavir, ritonavir, indinavir,
nelfinavir and have already been approved.

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52
 The most challenging problem associated with HIV
therapy is the development of drug resistance
 The combination therapy approach has been broadly
practiced in HIV treatment as a strategy to avoid such
problem
 Current efforts to develop new anti-HIV drugs are
now directed more toward developing inhibitors for
other steps in the virus life cycle, such as viral entry
into the T-cell, its integration with the host DNA, or
its assembly into daughter particles
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 The aim of anti-HIV therapy has now shifted from simply
delaying the progression of the disease to finding a
permanent cure
 We have now entered the area of highly active anti-
retroviral therapy (HAART)
 The current trend is to give a potent combination of agents
HAART right from the start when treatment is indicated

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 The most popular combination is Zidovudine (AZT) and
lamivudine plus a protease inhibitor
 Lamivudine has greater anti-retroviral activity than AZT
alone and is active against many AZT-resistant strains
without significant increase in toxicity
 Among protease inhibitors, indinavir (IDV) is more
potent than saquinavir and appears to have fewer drug
interactions and short-term adverse effects than
ritonavir
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10q

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