Classification and

Biochemistry of a Virus
• Considered as “Obligate Intracellular Parasites”
because: they are not living, metabolically inert
particles and requires a host cell in order to
reproduce.
• Viruses have no cell wall, ribosomes or
mitochondria.
• Virus is composed of CAPSID and a
NUCLEIC ACID making it unique and the
smallest of all self-replicating organisms
Classification and
Biochemistry of a Virus
• Viruses containing envelope – antigenic in
nature
• They do not have a metabolic machinery of
their own – uses host enzymes
• Certain viruses multiply in the cytoplasm
but others do in the nucleus
• Most multiplication take place before
diagnosis is made.
Classification and
Biochemistry of a Virus
• SHAPE: determined by arrangement
of capsomeres:
• Isometric or spherical eg. Icosahedral
• Helical or spiral shaped
• Filamentous or rod like
• Complex
Types of Virus
Classification and
Biochemistry of a Virus
Classification and
Biochemistry of a Virus
Classification and
Biochemistry of a Virus
Classification of Viruses
• Nucleic acid
• Viral Morphology
• Site of Replication in cell
• Coating
• Serological typing (antigenic signatures)
• Cell types infected (B-lymphocytes, T-
lymphocytes, monocytes)

Study the Baltimore Classification Scheme Table 9.1 pg 331

Protection/Prevention
against Viral Infection
• Innate immunity
• Chemoprophylaxis
 Infectious Process
of a Virus
1. ATTACHMENT
• Requires receptors (constitutes to tissue
tropism)
2. ENTRY
• Penetration into the host cell
3. UNCOATING
• Release of viral nucleic acid Virus enters the cell through endocytosis
 Infectious Process
of a Virus Naked Nucleic Acid (DNA or RNA)
1. ATTACHMENT
• Requires receptors (constitutes to tissue
tropism)
2. ENTRY
• Penetration into the host cell
3. UNCOATING
• Release of viral nucleic acid NUCLEUS

4. TRANSCRIPTION &
TRANSLATION mRNA is produced
• Viral nucleic acid is replicated &
expressed using HOST CELL
PROCESSES.
• Cell is irreversibly modified &
killed.
• Virus uses the cell’s own
manufacturing mechanism (most
crucial stage of viral replication. Production of Viral Proteins
CYTOPLASM
 Infectious Process
of a Virus
DNA & RNA Replication

Naked Nucleic Acid (DNA or RNA)

1. ATTACHMENT
2. ENTRY
3. UNCOATING
4. TRANSCRIPTION &
TRANSLATION
• Viral nucleic acid is replicated &
expressed using HOST CELL
PROCESSES.
5. ASSEMBLY DNA Polymerase
• Duplicated DNA or RNA of the NUCLEUS
virus & its proteins are assembled.

RNA Polymerase
Production of Viral Proteins
CYTOPLASM
 Infectious Process
of a Virus DNA & RNA Replication
Naked Nucleic Acid (DNA or RNA)
1. ATTACHMENT
2. ENTRY
3. UNCOATING
4. TRANSCRIPTION &
TRANSLATION
• Viral nucleic acid is replicated &
expressed using HOST CELL
PROCESSES.
5. ASSEMBLY DNA Polymerase
• Duplicated DNA or RNA of the NUCLEUS
virus & its proteins are assembled.

6. RELEASE
• Release by either budding from
the cell membrane (enveloped) or
rupture of the cell (non- RNA Polymerase
enveloped).
Production of Viral Proteins
CYTOPLASM
 TARGETS FOR
ANTI-VIRAL DRUGS
 TARGETS OF
ANTIVIRALS
VIRAL
1.

ENVELOPE/CAPSULE
• Primary Targets for
antibodies
TARGETS OF ANTIVIRALS
1. VIRAL ENVELOPE/CAPSULE
• Primary Targets for antibodies

2. ATTACHMENT
• Receptors may be blocked
(sialic acid derivatives, ligands
or anti-receptor antibodies)
• The process of production is
poorly understood and
kinetic parameters are not
well defined.
TARGETS OF ANTIVIRALS
1. VIRAL ENVELOPE/CAPSULE
• Primary Targets for antibodies
Hemmaglutinin
2. ATTACHMENT
• Receptors may be blocked NAM – N-acetylmuramic acid
(sialic acid derivatives, ligands PENETRATION
or anti-receptor antibodies)
M2 Proteins
3. PENETRATION /
UNCOATING
• Uncoating is largely mediated
by cellular enzymes,
• Penetration, is often influenced
by one or more virus proteins

• For Influenza virus, UNCOATING

inhibition of M2 protein
prevents viral penetration by
inhibiting membrane fusion.
TARGETS OF ANTIVIRALS

1. VIRAL ENVELOPE/CAPSULE
2. ATACHEMENT
3. PENETRATION/UNCOATING
4.REPLICATION
• Targets various polymerases
(HIV)
• Serve as polymerase substrates
to terminate replication.
(nucleoside analogues)
• Most nucleoside analogues are Pro-
drugs: requires viral polymerase,
NOT cell polymerase
ACYCLOVIR

TERMINATION OF THE DNA/RNA STRAND

Polymerases
ANTIVIRAL
DRUGS
Virucidal vs. Virostatic
• -cidal
• Disinfectants and detergents
• Destruction of host tissue by:
• Cryotherapy
• Laser therapy
• TCA
• Podophylllin
• -static
• Antiviral drugs (chemoprophylaxis,
nucleoside antimetabolites, etc,)
Common Problems on
Anti-viral Drugs
• -static
• Ineffective against non-replicating virus
• Limited spectrum of activity
• Resistance is common due to:
• Mutation
• Emergence of resistant subpopulation
• Seen on immunocompromised host (HIV)
• Toxicity
 Role of Anti-virals
• Enhance recovery from illness by reducing the
duration of symptoms: Primary HSV
• Inhibition of disease progression: HSV in
patient with CMI defects
• Supress latent state: decrease frequency of
recurrences: Secondary HSV or CMV
• Prevent vertical transmission of HIV or HSV
• Chemoprophylaxis in HBV, HCV, HIV (needle
prick)
Chemoprophylaxis influenza:
Amantadine and Rimantadine
• Tricyclic amine compounds
• Are related antiviral drugs in a class of
medications known as adamantanes/
adamantanamine agent.
• Inhibit an early step in viral replication, most
likely viral uncoating.
• In some strains: viral assembly by
interfering with hemagglutinin
processing.
Chemoprophylaxis influenza:
Amantadine and Rimantadine
• Inhibit replication of influenza A viruses at
low concentrations.
• Amantadine: Used for the treatment of
Parkinson disease; has greater CNS activity
(anticholinergic effects): anxiety, insomnia,
seizures
• Rimantadine (methylated amantadine): is
4-10 times more active than amantadine, has
great GI problems
Neuraminidase
Inhibitors
• Neuraminidase inhibitors prevent the
release of new virions and their spread from cell
to cell.
• Sialic acid analogues
• Spectrum of activity: Active against both
influenza A and B virus
• Zanamivir and Oseltamivir
• Toxicity: NV (Oseltamivir); Bronchospasms
(Zanamivir) CI to patient with COPD or asthma
 Anti-viral Drugs
• Interferons (IFNs) are natural proteins
produced by the cells of the immune systems
in response to challenges by foreign agents
such as viruses, bacteria, parasites and tumor
cells.
• Antiviral, immune modulating and anti-
proliferative actions
• Three classes of interferons – α , β, γ
 Anti-viral Drugs
• α and β interferons are produced by all
the cells in response to viral infections
• γ interferons are produced only by T
lymphocyte and NK cells in response to
cytokines – immune regulating effects
• γ has less anti-viral activity compared
to α and β interferons
 Anti-viral Drugs
• Induction of the following enzymes:
1. protein kinase which inhibits protein
synthesis
2. an oligo-adenylate synthase which
leads to degradation of viral mRNA
3. phosphodiesterase which inhibit
tRNA

The action of these enzymes leads to an

INHIBITION OF TRANSLATION
MOA: INTERFERONS
• Are CYTOKINES
produced by infected cells
• Elicit ANTIVIRAL STATE
in neighbouring cells or a
NK cell response to
DESTROY infected cell.

Interferons

INF attach to INF

receptors
(INF α & β)
ANTIVIRAL STATE
Activates NK cells • Viral penetration
(INF γ) • Synthesis of mRNA
• Translation of viral CHON
• Viral assembly/release
 Spectrum of Activity
Interferon α
• Includes HBV, HCV and HPV.
• Anti-proliferative actions may inhibit the
growth of certain cancers - like Kaposi
sarcoma and hairy cell leukemia.
Therapeutic uses Interferons
• Chronic hepatitis B and C, HZV infection in
cancer patients
• CMV infections in renal transplant patients
• Condylomata acuminata (given by intralesional
injection). Complete clearance is seen ~ 50%.
• Hairy cell leukemia (with Zidovudine)
• AIDS related Kaposi’s sarcoma
• Venereal warts, MS
 Toxicity: Interferons
•ƒ
Expected (occurs in 40%):
• Fever, headache, fatigue, arthralgia, myalgia,
anorexia, vomiting, & diarrhea
• Dose limiting:
• Cytopenias, neuropsychiatric, autoimmune
• Severe-Life threatening:
• Thyroid, visual, auditory, renal and cardiac
impairment, and pulmonary fibrosis
 PEG - Interferon
• 40 kDa branched chain polyethylene glycol
covalently bonded to interferon
• Results in sustained delivery and reduced
clearance of interferon
• Allows for once weekly dosing
• Decreases the development of interferon
resistance
• Similar safety profile re: non-PEG interferon
Nucleoside Analogues
Nucleoside Analogues
• Inhibitors of DNA polymerase
• Reverse transciptase inhibitors
• Miscellaneous (Ribavirin): used for
sever LRTI cause by RSV in carefully
selected hospitalized infants and
young children
Nucleoside Analogues
• Trifluridine/Idoxuridine/Vidarabine
• Foscarnet
• Acyclovir/Valacyclovir
• Famciclovir/Penciclovir
• Ganciclovir/Cidofovir
• Ribavirin
Trifluridine

THYMIDINE TRIFLURIDINE
Trifluridine
• MECHANISM OF ACTION
• Acts as substrate & inhibits
Viral DNA Polymerase
• Produce fragile, poorly
functioning DNA
• Causes miscoding errors for the
proteins
• It is useful for Primary Keratoconjunctivitis &
recurrent Epithelial Keratitis due to HSV 1 & 2.
• Spectrum of activity: HSV 1 & 2, VZV, CMV & some
adenovirus
Nucleoside Antimetabolites
IDOXURIDINE

THYMIDINE IDOXURIDINE
IDOXURIDINE
• Tx for HERPES
SIMPLEX KERATITIS
MECHANISM OF ACTION
• Acts as substrate & Inhibits Viral
DNA Polymerase
• Produce DNA w/ I2 which is more
brittle.
• Causes miscoding errors for the
proteins
I

Adenine Thymine
Idoxuridine Prone to Strand Breakage
 Transcriptase

IDOXURIDINE
• Tx for HERPES
SIMPLEX KERATITIS
MECHANISM OF ACTION
• Acts as substrate & Inhibits Viral
DNA Polymerase
• Produce DNA w/ I2 which is more
brittle.
• Causes miscoding errors for the
proteins
• LACKS SELECTIVITY

Miscoded mRNA = Faulty proteins

Adenine Idoxuridine
Vidarabine (ara-A)
• It is a 2’ epimer of natural adenosine

Adenosine Vidarabine
 Mechanism of Action
•Inhibits DNA synthesis
•The drug is converted to
its triphosphate analog
which inhibits viral
DNA-polymerase.
•Serves as chain
terminator
 Anti-viral Drugs
• Spectrum of activity: HSV-1, HSV-2 and
VZV.
• Uses:
• Its use is limited to HSV keratitis
(keratoconjunctivitis)
• Completely confined to DNA Viruses
• Alternative to Idoxuridine
• ADE: Anemia and SIADH
• Administration: Ophthalmic ointment
 Cytarabine
• MOA: blocks cellular utilization of
deoxycytidine, hence inhibiting the replication of
viral DNA
• Use: anti-cancer for Burkitt lymphoma and
myeloid&lymphatic leukemias
• DOC: for HSVs
• SAR: before it becomes active, the drug is
converted to monophosphate, diphosphate and
triphosphate which blocks DNA polymerase and
the C-2 reductase
 Foscarnet
• Trisodium
phosphonoformate:
organic analogue of
inorganic
pyrophosphate
• Does not require
biochemical
activation by viral or
cellular enzyme,
hence, can be used to
resistant strains of FOSCARNET
viruses.
Foscarnet

• MECHANISM OF
ACTION
• Non-competitive
inhibition of viral
DNA polymerase
• Cessation of the incorporation of
nucleoside triphosphates into the DNA
• Spectrum of Activity: HSV-1, HSV-2,
VZV, CMV and HIV.
 Mechanism of Resistance
• Since it doesn’t need intracellular
phosphorylation – thymidine kinase mutations in
HSV/VZV and UL97 mutations in CMV do not
produce foscarnet resistance
• Mutation in DNA polymerase
Foscarnet
• Adverse Effects:
• Hypocalcemia and hypomagnesemia
• Neurotoxicity (headache, hallucinations,
seizures)
• Nephrotoxicity (acute tubular nephritis,
interstitial nephritis)
Acyclovir and Congeners
• Acyclovir is a prototype anti-herpetic drug
• Acyclovir > Vidarabine
• AOC for HSV enceohalitis
• MOA: inhibitor of DNA polymerase 
chain termination
Acyclovir and Congeners
• Acyclovir, Valacyclovir, Ganciclovir,
Famciclovir, Penciclovir: guanine
nucleoside analogs.
• Valacyclovir: prodrug of Acyclovir with
better bioavailability.
• Famciclovir: hydrolyzed to Penciclovir
and has greatest bioavailability.
• Penciclovir: used only topically whereas
Famciclovir can be administered orally.
Acyclovir • Very selective (200 times affinity to
viral kinase than mammalian
enzyme

Acyclovir
OPEN CHAIN
SUGAR
 • Very selective (200 times
MOA: Acyclovir affinity to viral kinase than
mammalian enzyme
and Congeners
• Drugs are phosphorylated by
viral thymidine-kinase, then
metabolized by host cell kinases
to nucleotide analogs.
• The analog inhibits viral
DNA-polymerase
• Only actively replicating viruses
are inhibited
• USES: Limited to Herpes
Virus (DOC), Genital Herpes,
Shingles & Chicken Pox Termination of DNA Strand
 MOA: Acyclovir
and Congeners
• Intracellular uptake
• Triphosphorylation
• 1st via thymidine kinases in HSV
and VZV or phosphotransferases
in CMV (occurs in infected cells)
• 2nd and 3rd is by cellular kinases
• Competitive inhibition of dGTP
by DNA polymerases
ACYCLOVIR
• Terminates DNA chain
elongation after acyclovir
incorporation into viral DNA Termination of DNA Strand
 Acyclovir and Congeners
• Mechanism of Resistance:
• Major mechanism: Reduced or absence of
thymidine kinase
• Altered thymidine kinases
• Altered DNA polymerases
• Toxicity:
• N and V, Diarrhea
• Tremors, seizures
• Nephrotoxicity: Crystalluria, hematuria
• Myelosupression (Ganciclovir)
 Acyclovir and Congeners
• Activity: HSV>VZV>CMV>EMV
• Acyclovir: HSV-1, HSV-2, VZV, Shingles.
• Ganciclovir/Cidofovir: CMV
• Famciclovir: Herpes genitalis and
shingles
• Foscarnet: HSV, VZV, CMV, HIV
• Penciclovir: Herpes labialis
• Trifluridine: Herpetic
keratoconjunctivitis
 Acyclovir and Congeners
• Therapeutic uses:
• Acyclovir is the drug of choice for: HSV
Genital infections, HSV encephalitis, HSV
infections in immunocompromised patient
• Ganciclovir is the drug of choice for: CMV
retinitis in immunocompromised patient,
Prevention of CMV disease in transplant
patients
 Valacyclovir
USES: Tx of Herpes
Zoster (Shingles) in
Immunocompromised
pts.)
ACYCLOVIR

VALACYCLOVIR

Valyl Ester
Ganciclovir
A deoxyguanosine
ACYCLOVIR
analogue

Analogue of acyclovir
with an additional
HYDROXYMETHYL
GROUP on the acyl
GANCICLOVIR side chain.
Ganciclovir
• Mechanism of Action: Uses viral-encoded
phosphotransferase produced in CMV infected
cells for 1st phosphorylation
• Mechanism of Resistance: reduced cellular
phosphorylation; Viral DNA polymerase
mutations (cross resistance with cidofovir)
• SE/toxicity: bone marrow myelosupression,
Neutropenia, Thrombocytopenia, Anemia
• Uses: Toxicity Limits is use to Tx & suppress
Sight-Threatening CMV Retinitis in
Immunocompromised pts.
 GUANINE
Famciclovir and
Penciclovir
Famciclovir: diacetyl-6-deoxy analog of penciclovir
Penciclovir: guanine nucleoside analog, rapidly
metabolized to penciclovir by deacetylation in GUT
and liver

PENCICLOVIR

FAMCICLOVIR
Famciclovir and
Penciclovir
• Penciclovir is
similar to acyclovir
(except the side O2
is replaced with C &
an extra hydroxyl
group)
• Found longer in
tissues compared to PENCICLOVIR

acyclovir
Famciclovir and
Penciclovir
• MECHANISM OF
ACTION:
• Inhibits viral DNA synthesis
• Competes for viral DNA
Polymerase
• Not an obligate chain
PENCICLOVIR
terminator but inhibits DNA
elongation
• USES:
• Topical Tx of recurrent Herpes labialis (Cold Sores)
 Adefovir Dipivoxil
• MOA: inhibits HBV
DNA polymerase
which coeporates
into viral DNA and
causes chain
termination

• DOC for chronic

form of Hepatitis B
 Entecavir
• Guanosine analog
for HBV
• MOA: competes
with
deoxyguanosine
triphosphate, for
viral reverse
transcriptase
Telbivudine
• thymidine analog
• For HBV
• Eliminated by
glomerular filtration
• Dose adjustment is
needed for renal failure.
 Tenofovir
• NRTI
• HIV-1 and HBV
• Adenine analog
Cidofovir CYTOSINE

• A monophosphate nucleotide
analogue of dCTP
• Different from other
nucleoside analogue because it
is a Phosphonic Acid
Derivative. no
phosphorylation CIDOFOVIR

required.
• MECHANISM OF ACTION
• Inhibits viral DNA
Polymerase
• DNA Chain Terminator
Cidofovir CIDOFOVIR

• USES: Possesses high

therapeutic index against CMV
resistant to ganciclovir; tx for
CMV Retinitis in
immunocompromised pts. HSV
and VZV resistant to acyclovir
• ADR: Nephrotoxic (common)
• Pre-treatment with PROBENECID & prehydration
with IV NSS can be used to reduce nephrotoxicity
• MOR: No cross-resistance with ganciclovir UL97
mutation or resistance to foscarnet
 Ribavirin
• A synthetic guanosine analog
• MOA: after intracellular
phosphorylation the triphosphate
interferes with early stages of
viral transcription (capping and
elongation of mRNA)
• Decreases cellular GTP formation
• Inhibits RNA polymerase and Reverse
transcriptase
• Alters cellular pool of nucleotides and subsequent
mRNA formation.
 Ribavirin
• Spectrum of Activity: DNA and RNA viruses
• ADR/Toxicity: Anemia and jaundice. Not
advised during pregnancy.
• DOC for RSV bronchiolitis and pneumonia in
hospitalized children (given by aerosol) and
Lassa fever
• Alternative drug for influenza, para-influenza,
measles virus infection in
immunocompromised patients. Useful in HCV
with interferons
Fomivirsen
• Fomivirsen is
oligonucleotide
directed against
CMV mRNA
• Blocks translation
of CMV gene
• First anti-sense
anti-viral
 SUMMARY
DNA POLYMERASE
INHIBITORS
DNA Polymerase inhibitors
• Idoxuridine: non-selective, tx of herpes
simplex keratitis
• Trifluridine: DOC primary HSV
keratoconjunctivitis and recurrent
epithelial keratitis due to HSV 1 and 2
• Vidarabine: broad spectrum, alternative
for idoxuridine
• Acyclovir and valacyclovir: DOC for
Varicella zoster, chicken pox
DNA Polymerase inhibitors

• Ganciclovir: tx and supression of

sight threatening CMV retinitis in
immunocompromised patients
• Penciclovir: tx of recurrent Herpes
labialis
• Famciclovir: diacetyl prodrug of
penciclovir
DNA Polymerase inhibitors

• Cidofovir: tx of CMV retinitis in

AIDS patient. AE: renal impairment
• Foscarnet: 2nd line drug for the
treatment of CMV retinitis in AIDS
patients
REVERSE TRANSCRIPTASE
INHIBITORS
• Reverse transcriptase
converts the viral RNA into a
dsDNA, ready for integration
into the host chromosome
• All of the classical
antiretroviral agents are 2’3’-
dideoxy nucleoside analogues.
• Inhibitors of RT block ACUTE INFECTION of
cells but are only weakly active in
CHRONICALLY INFECTED ones.
 Zidovudine
• Has high affinity for HIV RT than for human DNA
Polymerase

3’ azido group
THYMIDINE ZIDOVUDINE (AZT)
 Zidovudine
• MECHANISM OF ACTION:
Competitively inhibits RT with
respect to thymidine triphosphate.

• USES: Recommended for the

management of adult pts.with
symptomatic HIV infections, with
3’ azido group
CD4+ count below 200/mm3 or
with history of Pneumocystis
carinii (opportunistic).

• ADR: Anemia & Granulocytopenia

Prevents further elongation of
limits AZT for asymptomatic pts. DNA strand, hence, the strand
will be terminated
Didanosine
• Purine Nucleoside Analogue
• Less potent compared to AZT
(10-100fold) but causes less
myelosuppression.
• Combined with AZT for
synergistic effects

DIDANOSINE
Didanosine
• MECHANISM OF ACTION
• Competitively inhibits RT
• Incorporated into the DNA to
causes DNA termination.
• USES
• Tx for pts with advanced HIV
infections
• ADR
• Painful peripheral neuropathy &
Pancreatitis.
• Food interferes with absorption.
Zalcitabine
• Analogue of cytosine
• Combined with AZT for the tx of adv HIV
infections
• Enters the cell through carrier-mediated
processes.

CYTOSINE ZALCITABINE
Zalcitabine
• MECHANISM OF ACTION
• Inhibits RT
• Cause DNA termination of
the elongating viral DNA
• USES
• Tx for pts with advanced HIV infections who are
intolerant to AZT alone.
• ADR
• Painful peripheral neuropathy & Pancreatitis
Stavudine
• Analogue of thymidine
• Acid stable & well absorbed (about 90%)
following oral administration.

THYMIDINE STAVUDINE
Stavudine
• MECHANISM OF ACTION
• Similar to AZT
• Inhibits RT
• Cause DNA termination of the
elongating viral DNA
• USES
• Tx for pts with advanced HIV infections who
are intolerant to other therapies
• ADR
• Peripheral neuropathy
Lamivudine
• Nucleoside analogue similar to ddC.
• It contains a substitution of sulfur atom in place of a
methylene group at the 3’ position of the ribose ing.
• More effective than ddC
• If combined with AZT, it increases the CD4+ counts
• MOA: similar to ddC

ZALCITABINE LAMIVUDINE
 SUMMARY
REVERSE
TRANSCRIPTASE
INHIBITORS
Reverse Transcriptase
Inhibitors
• Zidovudine (AZT): recommended for the
management of adult patients with
symptomatic HIV infection with history of
PCP
• Didanosine: recommended for AZT
intolerant advanced HIV infection
• Zalcitabine
• Lamivudine
Pleconaril
• Mechanism of Action: Inserts into pockets in
the surface of virions; interferes with interactions
of virus with cell receptors
• Spectrum of Activity: Broad spectrum =
Picornaviruses = Small RNA viruses (Interferes
with viral uncoating), Rhinovirus, Enteroviruses
(Coxsackie, Echovirus, Poliovirus), HAV
Agents for HIV infection
• HIV – Vaccine
▫ Generally safe and elicit a protective immune
response
▫ Stimulate both cellular and humoral immunity
▫ Protect components against all major HIV
subtypes
▫ Induce long lasting protection
▫ Induce local immunity
▫ Practical for worldwide delivery and
administration
Agents for HIV infection
• Question: it refers to the multidrug
regimen for HIV infection.
• NRTIs
• NNRTIs
• Protease inhibitors
• Entry inhibitors
• Integrase inhibitors
Agents for HIV infection
• Non-nucleoside Reverse
Transcriptase Inhibitors
(NNRTIs)
▫ Nevirapine
▫ Delaviridine
▫ Efavirenz
 NNRTIs
• Do not require
bioactivation
• Do not incorporate itself
into the growing DNA
chain.
• DISTORTS THE
ENZYME so that it
cannot form an enzyme-
substance complex.
• Inhibits HIC-1
selectively (not able to
inhibit other retrovirus)
 NNRTIs
• Have High TI (in
contrast to nucleosides)
& do not inhibit DNA
polymerase.
• Chief problem: Rapid
emergence of
resistance among HIV
isolates
• Requires combination of
NNRTIs with at least 2
additional
antiretroviral agents.
 NEVIRAPINE
• MOA: Transformed by P450
(Viramune®) (CYP) to inactivate
hydroxylated metabolites
• Undergo hepatic recycling
blocks the RNA-dependent
and DNA-dependent DNA
polymerase activities
• ADR: Rash (17%), Nausea &
vomiting, Category C drug for
pregnant women, Hepatitis
(8-18%), Risk is greatest in
• Readily absorbed (greater
first 6 weeks of therapy,
than 90%) after oral
Could be benign or fatal
administration
Nevirapine-Induced Rash

Courtesy of HIV Web Study, www.hivwebstudy.org

DELAVIRDINE (Rescriptor®)
• Used with at least two
additional antiretroviral
agent to treat HIV-1
infection
• 98% protein bound
• Rarely used as an AVR
• MECHANISM OF
ACTION
• Similar to NVP
• ADR: Rash
 EFAVIRENZ (Sustiva®)
• Mandated for use with at
least two antiretroviral
agents
• 99% protein bound
• Widely used NNRTI
• MOA: Similar to NVP
• Toxicity:CNS Changes (52%)
, Rash (15-27%) usually does
not require discontinuation;
Hepatotoxicity
 NNRTI Rash
• Often diffuse, slightly
raised, itchy
• Vary in redness and
distribution
• Can be severe -
Steven’s Johnson
Syndrome
Courtesy of the Public Health Image
Library/CDC/ J. Pledger, BSS/VD
Agents for HIV infection
• HIV Protease inhibitors
▫ Saquinavir
▫ Indinavir
▫ Ritonavir
▫ Amprenavir
▫ Nelfinavir
 HIV Protease Inhibitors
• Enzyme that cleaves gag-pro propeptides to
yield active enzymes that function in the
maturation & propagation of new virus.

Indinavir
HIV
Protease
Inhibitors
• ADR
Can cause
dyslipedemia
• Redistributes fats
causing protease
pouch, buffalo
hump, facial atrophy
& breast
enlargement.
• Can also cause
hyperglycemia
 New agents for HIV
infection
• HIV entry inhibitors
• Chemokine Receptor binders
• Inhibitors of GP41 Fusion
activity
• Integrase inhibitors
• siRNA
 HIV Entry Inhibitors
• Chemokine Receptor
Binders / Inhibition of
gp41 Fusion Activity
• gp120 mediates viral
attachment by binding
to host receptors.
• CD4+ & the chemokine
receptors
• gp41 acts as the
anchor for gp120 in the
virus
 Chemokine Receptor Binders
(CXCR4 & CCR5)
• Compound AMD-
3100
• 1st compound
identified as a
CXCR4-specific
inhibitor but not
of CCR5.
• Compound TAK-779
• Exhibits high
affinity for CCR5
coreceptors.
 Inhibition of gp41 fusion
Activity

• Pentafuside (T-20)
• Inhibits formation
of the fusion
component
conformation of
gp41.
 Integrase Inhibitors
• Has 2 closely related molecules
• BLOCKS STRAND TRANSFER catalysed by
integrase.
• DIKETO ACIDS
• Have high specific mechanism.
• Targets Integrase with IC50 less than 0.1μM
• TETRAZOLE DERIVATIVE
• Centered in the active site of an IN near acidic
catalytic residues.