Antiviral Drugs and their mechanism of action
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Feb 27, 2024
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About This Presentation
Antiviral drugs and their mechanism of action
Slide Content
Antiviral Drugs
Ajay Kumar Yadav
Scientist
Ajay Kumar Yadav
Scientist
History and Development of
Antiviral Drugs
Antiviral Drugs
History
•Late 1960s-Amantadine (Symmetrel)
•For Treatment of Influenza A Virus Infections
•MOA -Amantadine was not deduced until the
early 1990s
•Antiviral Discovery Program-
•“Hits”-for safety and efficacy
•“Leads”-to reduce toxicity, increase solubility and
bioavailability, or improve biological half-life.
Random chemicals and natural-product Mixtures-tested for their ability to block replication
of a variety of viruses in cell culture system
Blind Screening
•Late 1960s-Amantadine (Symmetrel)
•For Treatment of Influenza A Virus Infections
•MOA -Amantadine was not deduced until the
early 1990s
•Antiviral Discovery Program-
•“Hits”-for safety and efficacy
•“Leads”-to reduce toxicity, increase solubility and
bioavailability, or improve biological half-life.
Random chemicals and natural-product Mixtures-tested for their ability to block replication
of a variety of viruses in cell culture system
Blind Screening
Time line of antiviral drug discovery
Year Name of drug discovered Name of discoverer
1951β-Thiosemicarbazone Hamreet al.
1957Interferon Isaacs & Lindenmann
1958Idoxiuridine Dr Bill Prusoff
1961Hydroxybenzylbenzimidazole Tamm & Eggers
1961Guanidine Barrera-Oro & Melnick
1962IDU (clinical effectivenes) Kaufman
1963Marboran(clinicaleffectiveness) Bauer et al.
1964TFT (clinical effectiveness) Kaufman
1964 Amantadine Davies, Hoffmann et al.
1964 Ara-A Privat de Garilhe & De Rudder
Year Name of drug discovered Name of discoverer
1951β-Thiosemicarbazone Hamreet al.
1957Interferon Isaacs & Lindenmann
1958Idoxiuridine Dr Bill Prusoff
1961Hydroxybenzylbenzimidazole Tamm & Eggers
1961Guanidine Barrera-Oro & Melnick
1962IDU (clinical effectivenes) Kaufman
1963Marboran(clinicaleffectiveness) Bauer et al.
1964TFT (clinical effectiveness) Kaufman
1964 Amantadine Davies, Hoffmann et al.
1964 Ara-A Privat de Garilhe & De Rudder
Year Name of drug discovered Name of discoverer
1971 Ribavirin Sidwell, Robins et al.
1976 Ara-A (clinical effectiveness) Whitley
1977 Acyclovir Elion,Schaeffer, Collins, Bauer
1978 DHPA De Clercq& Holy
1978 Phosphonoformicacid Helgstrand& Öberg
1978 BVDU De Clercqet al.
1982 Ganciclovir Verheyden & C. Martin
1985 Azidothymidine(AZT) Mitsuya, Broderet al.
1986 ddI, ddC Mitsuya& Broder
1986 Adefovir De Clercq, Holy et al.
1971 Ribavirin Sidwell, Robins et al.
1976 Ara-A (clinical effectiveness) Whitley
1977 Acyclovir Elion,Schaeffer, Collins, Bauer
1978 DHPA De Clercq& Holy
1978 Phosphonoformicacid Helgstrand& Öberg
1978 BVDU De Clercqet al.
1982 Ganciclovir Verheyden & C. Martin
1985 Azidothymidine(AZT) Mitsuya, Broderet al.
1986 ddI, ddC Mitsuya& Broder
1986 Adefovir De Clercq, Holy et al.
Year Name of ofdrug discovered Name of discoverer
1987 Cidofovir De Clercq, Holyet al.
1989 Famciclovir Harnden, VereHodge
1989HEPT/TIBO De Clercq,Baba, Pauwels
1990Saquinavir J.A. Martin, Roberts
19913TC Belleau et al.
1993 Tenofovir Balzarini, De Clercq& Holy
1993 Relenza von Itzstein et al.
1997 Oseltamivir Kim et al.
1987 Cidofovir De Clercq, Holyet al.
1989 Famciclovir Harnden, VereHodge
1989HEPT/TIBO De Clercq,Baba, Pauwels
1990Saquinavir J.A. Martin, Roberts
19913TC Belleau et al.
1993 Tenofovir Balzarini, De Clercq& Holy
1993 Relenza von Itzstein et al.
1997 Oseltamivir Kim et al.
Drug development can be divided into four phases:
1.Discovery
2.Preclinical studies
3.Clinical development and
4.Market approval
Four phases of drug development
1.Discovery
2.Preclinical studies
3.Clinical development and
4.Market approval
Four phases of drug development
Discovering Antiviral Compounds
The New Lexicon of Antiviral Discovery
1.Rational Drug Designing (Development of drugs based on the study
of the structures and functions of target molecules)
2.In Silico Screening (mass spectrometry, fragment screening, nuclear
magnetic resonance (NMR) screening, DNA encoded chemical
libraries, high throughput screening (HTS)
3.High-throughput Screenings (HTS is a high-tech way to hasten the
drug discovery process, allowing quick and efficient screening of
large compound libraries at a rate of a few thousand compounds per
day or per week)
4.Cell-based Assays (Used in both biomedical research and drug-
discovery screening applications to efficiently quantify cytotoxicity,
biological activity, biochemical mechanisms and off-target
interactions)
5.Small Interfering RNA Screenings (Short interfering RNAs
(siRNAs) can be used to validate genomic drug targets)
The New Lexicon of Antiviral Discovery
1.Rational Drug Designing (Development of drugs based on the study
of the structures and functions of target molecules)
2.In Silico Screening (mass spectrometry, fragment screening, nuclear
magnetic resonance (NMR) screening, DNA encoded chemical
libraries, high throughput screening (HTS)
3.High-throughput Screenings (HTS is a high-tech way to hasten the
drug discovery process, allowing quick and efficient screening of
large compound libraries at a rate of a few thousand compounds per
day or per week)
4.Cell-based Assays (Used in both biomedical research and drug-
discovery screening applications to efficiently quantify cytotoxicity,
biological activity, biochemical mechanisms and off-target
interactions)
5.Small Interfering RNA Screenings (Short interfering RNAs
(siRNAs) can be used to validate genomic drug targets)
6. Combinatorial Chemistry- Combinatorial chemistry isa synthesis
strategy that enables the simultaneous production of large numbers of related
compounds.
These sets are referred to as libraries and they can be used in any discovery
project associated with high-throughput analysis capabilities
Set of compounds
“Libraries”
strategy that enables the simultaneous production of large numbers of related
compounds.
These sets are referred to as libraries and they can be used in any discovery
project associated with high-throughput analysis capabilities
Set of compounds
“Libraries”
•Viral targets-proof of principle
•Host targets-using RNA interference technologyGenetics and
Drug Discovery
•Bacterially based screen
•Mini replicon (replication, transcription,
movement, and host factors involved in
interactions between the virus and the host)
Cell-Based
Screens
•Very large numbers of compounds in an
automated fashion
•High-content Screens
High throughput
Screens
•Molecular mechanism-predicted i.e.,
specific viral encoded enzyme
Mechanism-
Based Screens
Screening for Antiviral Compounds
•Host targets-using RNA interference technologyGenetics and
Drug Discovery
•Bacterially based screen
•Mini replicon (replication, transcription,
movement, and host factors involved in
interactions between the virus and the host)
Cell-Based
Screens
•Very large numbers of compounds in an
automated fashion
•High-content Screens
High throughput
Screens
•Molecular mechanism-predicted i.e.,
specific viral encoded enzyme
Mechanism-
Based Screens
Screening for Antiviral Compounds
Sources of Chemical Compounds Used in Screening
Large libraries of chemical compounds
Natural products collected from all over the world
Using combinatorial chemistry
•Combinatorial chemistry is a synthesis strategy that enables the
simultaneous production of large numbers of related
compounds.
•These sets are referred to as libraries and they can be used in any
discovery project (drug) associated with high-throughput analysis
capabilities.
Large libraries of chemical compounds
Natural products collected from all over the world
Using combinatorial chemistry
•Combinatorial chemistry is a synthesis strategy that enables the
simultaneous production of large numbers of related
compounds.
•These sets are referred to as libraries and they can be used in any
discovery project (drug) associated with high-throughput analysis
capabilities.
•A “Hit” is any compound that has binding activity to the biological
target.
•A “Lead” is a compound with pharmacological activity that still
needs to be optimized for therapeutic effect and safety profile.
Hits Leads
target.
•A “Lead” is a compound with pharmacological activity that still
needs to be optimized for therapeutic effect and safety profile.
Hits Leads
Path of drug discovery
Diseases?
Diseases?
Designer Antivirals & Computer-Based Searching
Structure-Based Drug Design1
3
2Genome Sequencing Provides New
Information for Antiviral Drug Discovery
In-Silico Drug Discovery
• Discovery of Omics
• Systematic testing of chemicals
+ their interaction with protein structure
•Active site of protein target designed
– Small site,
– Fits into the pocket,
– By docking (The goal of ligand-protein docking is to predict
the predominant binding mode of a ligand with a protein of
known three-dimensional structure)
X-Ray crystallography
RNA interference tech
Structure-Based Drug Design1
3
2Genome Sequencing Provides New
Information for Antiviral Drug Discovery
In-Silico Drug Discovery
• Discovery of Omics
• Systematic testing of chemicals
+ their interaction with protein structure
•Active site of protein target designed
– Small site,
– Fits into the pocket,
– By docking (The goal of ligand-protein docking is to predict
the predominant binding mode of a ligand with a protein of
known three-dimensional structure)
X-Ray crystallography
RNA interference tech
Antiviral Drugs are Expensive to Discover, Develop, and Bring to the
Market
The Difference between “R” and “D”
Antiviral Drugs Must Be Safe
Drug Formulation and Delivery
-“R” of “R&D,” =beginning of the process of producing a drug
-“D” of “R&D” = development
It takes 5 to 10 years
Toxicity
Market
The Difference between “R” and “D”
Antiviral Drugs Must Be Safe
Drug Formulation and Delivery
-“R” of “R&D,” =beginning of the process of producing a drug
-“D” of “R&D” = development
It takes 5 to 10 years
Toxicity
Number of
compounds
Investment
required
The Development Pathway for novel drugs
compounds
Investment
required
The Development Pathway for novel drugs
1.Narrow antiviral spectrum-Each antiviral only works against a specific virus.
2.Viruses being intracellular are harder to target, antiviral drugs are more challenging
to develop.
3.There are more viruses than antiviral drugs to treat them.
4.Ineffectiveness against the latent virus
5.Development of drug-resistant mutants and toxic side effects
6.Antivirals are toxic because it lacks specificity, i.e. the drug inhibits host DNA
synthesis as well as that of the virus.
Limitations of Antiviral Drugs
2.Viruses being intracellular are harder to target, antiviral drugs are more challenging
to develop.
3.There are more viruses than antiviral drugs to treat them.
4.Ineffectiveness against the latent virus
5.Development of drug-resistant mutants and toxic side effects
6.Antivirals are toxic because it lacks specificity, i.e. the drug inhibits host DNA
synthesis as well as that of the virus.
Limitations of Antiviral Drugs
DRUGS INHIBITING VIRAL ATTACHMENT &
UNCOATING
UNCOATING
DRUGS INHIBITING VIRAL ATTACHMENT & ENTRY
Drugs inhibiting viral attachment
Receptor Co -receptorFusion of viral & cell membrane
Attachment of
the viral gp120
to the CD4
+
T
cell receptorBinding of the gp120 to CCR5 or
CXCR4 co-receptors
Enfuvirtide
Ibalizumab
Vicriviroc
Drugs inhibiting viral attachment
Receptor Co -receptorFusion of viral & cell membrane
Attachment of
the viral gp120
to the CD4
+
T
cell receptorBinding of the gp120 to CCR5 or
CXCR4 co-receptors
Enfuvirtide
Ibalizumab
Vicriviroc
HIV ENTRY PROCESS
CCR5/CXR4
CD4
+
-gp120
binding
gp120-co-receptor interaction
Viral & cell membrane fusion
CCR5/CXR4
CD4
+
-gp120
binding
gp120-co-receptor interaction
Viral & cell membrane fusion
CD4-gp120 BINDING INHIBITORS
PRO-542
Fusion protein that mimics CD4
+
domain.
Binds with gp120 & inhibits its binding with
CD4
+
TNX-355
Monoclonal antibody against CD4
+
Reduces plasma HIV-1 RNA load &
increases CD4
+
T cell level
BMS-806
Binds to V-1 loop of gp120
Blocks confirmational change
induced in gp120 after CD4
+
binding
VARIABLE DOMAINS OF gp120
PRO-542
Fusion protein that mimics CD4
+
domain.
Binds with gp120 & inhibits its binding with
CD4
+
TNX-355
Monoclonal antibody against CD4
+
Reduces plasma HIV-1 RNA load &
increases CD4
+
T cell level
BMS-806
Binds to V-1 loop of gp120
Blocks confirmational change
induced in gp120 after CD4
+
binding
VARIABLE DOMAINS OF gp120
RESISTANCE TO CD4-gp120 BINDING INHIBITORS
HIV gp120 glycoprotein with constant & variable domain
➢Change in the sequence of domains mainly V1, V2, V3
induces resistance
Changes in gp120 residues Trp-112, Thr-257, Ser-375,
Phe-382, Met-426, Met-434 and Met-475 resulted in BMS-
806 resistance
100 200 300 400 500
HIV gp120 glycoprotein with constant & variable domain
➢Change in the sequence of domains mainly V1, V2, V3
induces resistance
Changes in gp120 residues Trp-112, Thr-257, Ser-375,
Phe-382, Met-426, Met-434 and Met-475 resulted in BMS-
806 resistance
100 200 300 400 500
CCR5 ANTAGONISTS
CONFIRMATIONAL
CHANGE IN gp120
Transmembrane domain
CCR5
Competitive binding of drugs from RANTES
Drug molecule
V3 LOOP OF
gp120
INTERACT
WITH CCR5
CONFIRMATIONAL
CHANGE IN gp120
Transmembrane domain
CCR5
Competitive binding of drugs from RANTES
Drug molecule
V3 LOOP OF
gp120
INTERACT
WITH CCR5
CCR5 ANTAGONISTS
SR.No. DRUG MOA
1. VICRIVIROC Binds to transmamembrane
domain of CCR5
2. APLAVIROC Binds to extracellular
domain of CCR5
3. MARAVIROC Binds to transmamembrane
domain of CCR5
4. PRO-140 Binds to transmamembrane
domain of CCR5
CXCR4 ANTAGONISTS
SRNo. DRUG MOA
1. AMD070 Bindsto CXCR4
2. KRH-1636 Binds to extracellular
domain of CXCR4
SR.No. DRUG MOA
1. VICRIVIROC Binds to transmamembrane
domain of CCR5
2. APLAVIROC Binds to extracellular
domain of CCR5
3. MARAVIROC Binds to transmamembrane
domain of CCR5
4. PRO-140 Binds to transmamembrane
domain of CCR5
CXCR4 ANTAGONISTS
SRNo. DRUG MOA
1. AMD070 Bindsto CXCR4
2. KRH-1636 Binds to extracellular
domain of CXCR4
FUSION INHIBITORS
Host cell membrane Chemokine receptor Fusion peptide Enfuvirtide
Viral mem.(env.) Intermediate Trapped intermediate
Hemifusion stalk Fusion pore
✓Interaction between HR1 and HR2 forms a thermostable, six-helix
bundle structure(hemifusion stalk) which is critical for the viral and
cellular membrane fusion & formation of pore.
Host cell membrane Chemokine receptor Fusion peptide Enfuvirtide
Viral mem.(env.) Intermediate Trapped intermediate
Hemifusion stalk Fusion pore
✓Interaction between HR1 and HR2 forms a thermostable, six-helix
bundle structure(hemifusion stalk) which is critical for the viral and
cellular membrane fusion & formation of pore.
ENFURVITIDE (T-20)
TRADE NAME: FUZEON
INDICATIONS: USED FOR HIV-1
SIDE EFFECTS: Neuropathy, Insomnia,
Depression, Glomerulonrphritis
APPROVED BY FDA: MARCH13,2OO3.
ENFUVIRTIDE : FIRST HIV-1 FUSION INHIBITOR
T-1249
Enfuvirtide mimic HR-2 in
structure & binds with HR-1
Blocks formation of
hemifusion stalk
No membrane fusion
Mimic HR-2 in structure & binds with HR-1
39 amino acid peptide
TRADE NAME: FUZEON
INDICATIONS: USED FOR HIV-1
SIDE EFFECTS: Neuropathy, Insomnia,
Depression, Glomerulonrphritis
APPROVED BY FDA: MARCH13,2OO3.
ENFUVIRTIDE : FIRST HIV-1 FUSION INHIBITOR
T-1249
Enfuvirtide mimic HR-2 in
structure & binds with HR-1
Blocks formation of
hemifusion stalk
No membrane fusion
Mimic HR-2 in structure & binds with HR-1
39 amino acid peptide
RESISTANCE TO ENFURVITIDE (T-20)
✓RESISTANCE DUE TO MUTATION IN CODONS FROM 36-
45 WITHIN HR-1 LOOP
✓RESISTANCE DUE TO MUTATION IN CODONS FROM 36-
45 WITHIN HR-1 LOOP
PLECONARIL
Mechanism of Action
Pleconaril binds hydrophobic pocket
in VPI by noncovolent hydrophobic
interactions between position 152-
191 in pocket
Conformational changes
ability to intreract with receptor
Hydrophobic pocket of VP1
Pleconaril
Resistance
Mutation:
Position 152 : Tyr by Phe
Position191 : Val by Leu
For Enterovirus &
Rhinovirus infection
Indication:
Enterovirus
Mechanism of Action
Pleconaril binds hydrophobic pocket
in VPI by noncovolent hydrophobic
interactions between position 152-
191 in pocket
Conformational changes
ability to intreract with receptor
Hydrophobic pocket of VP1
Pleconaril
Resistance
Mutation:
Position 152 : Tyr by Phe
Position191 : Val by Leu
For Enterovirus &
Rhinovirus infection
Indication:
Enterovirus
MECHANISM OF ACTION OF AMANTIDINE & RIMANTADINE
MATRIX PROTEIN M2
INFLUENZA VIRUS
M2 : Matrix protein
Proton selective ion channel in envelope.
Contain 4 transmemebrane helices which
forms pore
Influx of H+ IONS through the pore
Dissociation of RNP from M1
RNP transported to nucleus & transcribed.
Amantadine binds to transmembrane domain
Binds in the middle of pore surrounding
residues
Val27, Ala 30, Ser31 , Gly34
Block the channel sterically
M2 PROTEIN IN DRUG ACTION
INFLUENZA VIRUS
M2 : Matrix protein
Proton selective ion channel in envelope.
Contain 4 transmemebrane helices which
forms pore
Influx of H+ IONS through the pore
Dissociation of RNP from M1
RNP transported to nucleus & transcribed.
Amantadine binds to transmembrane domain
Binds in the middle of pore surrounding
residues
Val27, Ala 30, Ser31 , Gly34
Block the channel sterically
M2 PROTEIN IN DRUG ACTION
AMANTADINE
Trade name : Symmetrel
Chemical name: 1-Adamantylamine
Indications: Used for treatment of Influenza
Adverse effects: Seizures, Nervousness, Anxiety, Agitation, Insomnia,
Skin rashes
APPROVED BY FDA: Oct. 1966 FOR INFLUENZA
RIMANTADINE
Trade name : Flumadine
APPROVED BY FDA: 1994 FOR INFLUENZA
Adverse effects: Seizures,Tiredness, Difficulty in concentrating
Trade name : Symmetrel
Chemical name: 1-Adamantylamine
Indications: Used for treatment of Influenza
Adverse effects: Seizures, Nervousness, Anxiety, Agitation, Insomnia,
Skin rashes
APPROVED BY FDA: Oct. 1966 FOR INFLUENZA
RIMANTADINE
Trade name : Flumadine
APPROVED BY FDA: 1994 FOR INFLUENZA
Adverse effects: Seizures,Tiredness, Difficulty in concentrating
•Zanamivir (Relenza) is aneuraminidase inhibitor
The mechanism of action of this drug is bybinding to the active site of
the neuraminidase protein.
Route-Inhalation
•Oseltamivir (Tami flu) neuraminidase inhibitor
Route-Oral administration
Neuraminidase Inhibitors
Oseltamivir Vs Zanamivir
Oseltamivir is a prodrug that
is metabolized to its active
form, oseltamivir
carboxylate, after oral
administration, while
zanamivir is designed for
delivery by inhalation.
Approved by the US Food and Drug Administration
for the treatment of influenza A and influenza B
The mechanism of action of this drug is bybinding to the active site of
the neuraminidase protein.
Route-Inhalation
•Oseltamivir (Tami flu) neuraminidase inhibitor
Route-Oral administration
Neuraminidase Inhibitors
Oseltamivir Vs Zanamivir
Oseltamivir is a prodrug that
is metabolized to its active
form, oseltamivir
carboxylate, after oral
administration, while
zanamivir is designed for
delivery by inhalation.
Approved by the US Food and Drug Administration
for the treatment of influenza A and influenza B
Inhibitors of Viral DNA replication
and late viral mRNA
and late viral mRNA
Introduction
•Most antiviral drugs inhibit viral genome replication
•Important target is the DNA polymerase
•Majority are nucleoside analogues, few are non-nucleoside
inhibitors
•Most antiviral drugs inhibit viral genome replication
•Important target is the DNA polymerase
•Majority are nucleoside analogues, few are non-nucleoside
inhibitors
Inhibitors of Viral DNA replication
•Aphidicolin
•Foscarnet
•HPMPA
•Brivudine
•Thiosemicarbazone
•Rifampicin
•Acyclovir
•Idoxuridine
•Vidarabine
•Cytarabine
•Campothecin
•Streptonigrin
•Trifluorothymidine
•Aphidicolin
•Foscarnet
•HPMPA
•Brivudine
•Thiosemicarbazone
•Rifampicin
•Acyclovir
•Idoxuridine
•Vidarabine
•Cytarabine
•Campothecin
•Streptonigrin
•Trifluorothymidine
Aphidicolin
•Natural aphidicolin is a secondary metabolite of
the fungusNigrospora oryzae.
•It is a specific inhibitor ofDNA polymeraseA
•Competes with each of dntps
•inhibition proceeds through the formation of a
pol -DNA-aphidicolin ternary complex
•Natural aphidicolin is a secondary metabolite of
the fungusNigrospora oryzae.
•It is a specific inhibitor ofDNA polymeraseA
•Competes with each of dntps
•inhibition proceeds through the formation of a
pol -DNA-aphidicolin ternary complex
Foscarnet
•(Trisodium phosphonoformate) is a pyrophosphate analog.
•Binds reversibly near the pyrophosphate-binding site of DNA
polymerase
•Blocks the cleavage of the pyrophosphate moiety from
deoxynucleotide triphosphates, in turn halting DNA chain
elongation.
•inhibition of mammalian DNA polymerase requires a 100-fold
greater concentration of foscarnet
•(Trisodium phosphonoformate) is a pyrophosphate analog.
•Binds reversibly near the pyrophosphate-binding site of DNA
polymerase
•Blocks the cleavage of the pyrophosphate moiety from
deoxynucleotide triphosphates, in turn halting DNA chain
elongation.
•inhibition of mammalian DNA polymerase requires a 100-fold
greater concentration of foscarnet
•Foscarnet is not activated by viral protein kinases,
making it useful in aciclovir-or ganciclovir-resistant HSV
and CMV infections.
•Acyclovirorganciclovir can develop mutant protein
kinases (thymidine kinase)
•Side effects
•Nephrotoxicity-Increase in serum creatinine levels.
•Electrolytedisturbances -Changes in calcium,
magnesium conc.
•CNS -Paraesthesias, irritability and hallucinations
making it useful in aciclovir-or ganciclovir-resistant HSV
and CMV infections.
•Acyclovirorganciclovir can develop mutant protein
kinases (thymidine kinase)
•Side effects
•Nephrotoxicity-Increase in serum creatinine levels.
•Electrolytedisturbances -Changes in calcium,
magnesium conc.
•CNS -Paraesthesias, irritability and hallucinations
Brivudine
•Bromovinyl deoxyuridine
•Similar toacyclovir
•was first synthesized at theUniversity of
BirminghamUK in the 1970s.
•potent inhibitor of theHSV-1 as well asVZV
•Bromovinyl deoxyuridine
•Similar toacyclovir
•was first synthesized at theUniversity of
BirminghamUK in the 1970s.
•potent inhibitor of theHSV-1 as well asVZV
•Mechanism of Action
•Analogue of thethymidine
•incorporated into the viral DNA, blocks the action of
DNApolymerases, thus inhibiting viral replication.
•Active compound is the 5'-triphosphate of BVDU
formed phosphorylations by viral thymidine kinase.
•Bridic, Brivox, Brivudin, Helpin, Zonavir and Zostex.
•Analogue of thethymidine
•incorporated into the viral DNA, blocks the action of
DNApolymerases, thus inhibiting viral replication.
•Active compound is the 5'-triphosphate of BVDU
formed phosphorylations by viral thymidine kinase.
•Bridic, Brivox, Brivudin, Helpin, Zonavir and Zostex.
•HPMPA
•(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl) adenine,
•First of the nucleoside phosphonate drugs described
•active metabolite (S)-HPMPA diphosphate by cellular
kinases .
•(S )-HPMPApp is an analog of dATPinhibiting DNA
replication
•Herpesviruses, vaccinia virus, and adenovirus,
•(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl) adenine,
•First of the nucleoside phosphonate drugs described
•active metabolite (S)-HPMPA diphosphate by cellular
kinases .
•(S )-HPMPApp is an analog of dATPinhibiting DNA
replication
•Herpesviruses, vaccinia virus, and adenovirus,
•Thiosemicarbazones
•Organosulfur compound with the formula H₂NCNHN=CR₂
•The first true antiviral agents discovered was the
thiosemicarbazones
•p-aminobenzaldehydethiosemicarbazone was the first
antiviral agent, found in 1950
•1-methylisatin 3-thiosemicarbazone, better known as
methisazone
•It is active against vaccinia virus (VV) .
•Organosulfur compound with the formula H₂NCNHN=CR₂
•The first true antiviral agents discovered was the
thiosemicarbazones
•p-aminobenzaldehydethiosemicarbazone was the first
antiviral agent, found in 1950
•1-methylisatin 3-thiosemicarbazone, better known as
methisazone
•It is active against vaccinia virus (VV) .
•Rifampicin
•Effective againstvacciniavirus
•Inhibits DNA-dependentRNA polymerase.
•binds to RNA polymerase at a site adjacent to the RNA
polymerase active center
•blocks RNA synthesis by preventing extension of RNA
products beyond a length of 2-3 nucleotides
•Resistance arises from
•Mutations altering residues of the rifampicin binding site on
RNA polymerase, resulting in decreased affinity for
rifampicin.
•Effective againstvacciniavirus
•Inhibits DNA-dependentRNA polymerase.
•binds to RNA polymerase at a site adjacent to the RNA
polymerase active center
•blocks RNA synthesis by preventing extension of RNA
products beyond a length of 2-3 nucleotides
•Resistance arises from
•Mutations altering residues of the rifampicin binding site on
RNA polymerase, resulting in decreased affinity for
rifampicin.
Acyclovir(ACV)
•Guanosineanalogue
•Active against –HSV-1, VZV
•Resistance to acicloviris rare
•Valacyclovir-prodrugof acyclovir, better oral
availability
•Other Guanosineanalogue-Penciclovir, famciclovir
•Ganciclovirand valganciclovir-treatment of HCMV
•Guanosineanalogue
•Active against –HSV-1, VZV
•Resistance to acicloviris rare
•Valacyclovir-prodrugof acyclovir, better oral
availability
•Other Guanosineanalogue-Penciclovir, famciclovir
•Ganciclovirand valganciclovir-treatment of HCMV
Idoxuridne(IUdR)
•Nucleoside analogue
•Incorporated into DNA during replication & blocks
base pairing
•Used in herpes viral infection
•Cardiotoxic-only topical use (herpes simplex keratits)
•0.5% ophthalmic ointment or as a 0.1% ophthalmic
solution
•Nucleoside analogue
•Incorporated into DNA during replication & blocks
base pairing
•Used in herpes viral infection
•Cardiotoxic-only topical use (herpes simplex keratits)
•0.5% ophthalmic ointment or as a 0.1% ophthalmic
solution
Trifluorothymidine
•Nucleoside analogue
•Triphosphatederivative get in cooperated into
DNA and inhibit base pairing
•Herpes infection-opthalmicsolution
•Also anti cancer drug
•Nucleoside analogue
•Triphosphatederivative get in cooperated into
DNA and inhibit base pairing
•Herpes infection-opthalmicsolution
•Also anti cancer drug
Vidarabine(ara-A)
•Adenine arabinoside-analogue of adenosine with the D-
ribose sugar, replaced with D-arabinose
•Originally intended as an anti-cancer drug
•Converted to triphosphatethat inhibit and also act as
substrate of DNA polymerase-replace adenosine bases
•Active against herpes viruses(VZV), poxviruses,
hepadnavirusesetc..
•Less susceptible to the development of drug resistance
•Adenine arabinoside-analogue of adenosine with the D-
ribose sugar, replaced with D-arabinose
•Originally intended as an anti-cancer drug
•Converted to triphosphatethat inhibit and also act as
substrate of DNA polymerase-replace adenosine bases
•Active against herpes viruses(VZV), poxviruses,
hepadnavirusesetc..
•Less susceptible to the development of drug resistance
Cytarabine (ArabinofuranosylCytidine, araC)
•Anticancer agent
•Also called cytosine arabinoside
•Inhibit use of deoxycytidineuse
•HSV, VZV, CMV
•Highly toxic-myelosuppressive, immunosuppressive
•Anticancer agent
•Also called cytosine arabinoside
•Inhibit use of deoxycytidineuse
•HSV, VZV, CMV
•Highly toxic-myelosuppressive, immunosuppressive
Camptothecin(CPT)
•Cytotoxicquinolonealkaloid, inhibit DNA
topoisomeraseI
•Bark of tree Camptothecaacuminata
•Introduced as anticancer drug
•Potent inhibitor of replication of adeno-, herpes-,
parvo-and papavoviruses
•Cytotoxicquinolonealkaloid, inhibit DNA
topoisomeraseI
•Bark of tree Camptothecaacuminata
•Introduced as anticancer drug
•Potent inhibitor of replication of adeno-, herpes-,
parvo-and papavoviruses
Streptonigrin
•Antibiotic from Streptomycesflocculus
•Anti-tumourdrug
•Double stranded DNA breaks are made
•Highly toxic-limited use as antiviral agent
•Antibiotic from Streptomycesflocculus
•Anti-tumourdrug
•Double stranded DNA breaks are made
•Highly toxic-limited use as antiviral agent
Azauridine
•6-azauracil riboside
•Anticancer agent
•Interfere with pyrimidinemetabolism
•6-azauracil riboside
•Anticancer agent
•Interfere with pyrimidinemetabolism
Inhibitors of Viral RNA genome synthesis
Inhibitors of Viral RNA genome synthesis
1.Guanidine
2.Gliotoxin
3. Hydroxybenzylbenzimidazole(HBB)
4. Ribavirin(Virazole)
5. Zidovudine(INN) or Azidothymidine(AZT)
6. Dideoxycytidine/ Zalcitabine
1.Guanidine
2.Gliotoxin
3. Hydroxybenzylbenzimidazole(HBB)
4. Ribavirin(Virazole)
5. Zidovudine(INN) or Azidothymidine(AZT)
6. Dideoxycytidine/ Zalcitabine
1.Guanidine
•Formed by oxidation of guanine
•It is found in urine as a normal product of protein metabolism
•Guanidiniumcation[CH
6N
3]
+
•Guanidine is protonatedin physiological conditions. This conjugate
acid is called the guanidiniumcation
•It acts on 2C Protein of Picornaviruses
•Selectively Inhibit poliovirus positive-stranded RNA synthesis
•Derivatives of Guanidine
Arginine
Triazabicyclodecene
Saxitoxin
guanidinium hydroxide
•Formed by oxidation of guanine
•It is found in urine as a normal product of protein metabolism
•Guanidiniumcation[CH
6N
3]
+
•Guanidine is protonatedin physiological conditions. This conjugate
acid is called the guanidiniumcation
•It acts on 2C Protein of Picornaviruses
•Selectively Inhibit poliovirus positive-stranded RNA synthesis
•Derivatives of Guanidine
Arginine
Triazabicyclodecene
Saxitoxin
guanidinium hydroxide
2.Gliotoxin
•Gliotoxinis a sulfur-containing mycotoxinbut having
antiviral activity (influenza, parainfluenza, Picornavuruses)
•Gliotoxindoes not show selectivity
•Interferes with the synthesis of both minus and plus-strand
RNA synthesis of RNA viruses
•Gliotoxininhibit the activity of 3DPol (RdRp)-Poliovirus
•Gliotoxinpossesses immunosuppressive properties and it
may cause apoptosis
•Gliotoxinis a sulfur-containing mycotoxinbut having
antiviral activity (influenza, parainfluenza, Picornavuruses)
•Gliotoxindoes not show selectivity
•Interferes with the synthesis of both minus and plus-strand
RNA synthesis of RNA viruses
•Gliotoxininhibit the activity of 3DPol (RdRp)-Poliovirus
•Gliotoxinpossesses immunosuppressive properties and it
may cause apoptosis
3.Hydroxybenzyl
benzimidazole(HBB)
•Selectively inhibits many members of the Picornavirusgroup
•HBBdoes not interfere with early virus-cell interactions.
•It specificlyinhibits viral RNA synthesis
•But inhibition of viral polypeptide synthesis appears to be a
secondary effect due to inhibition of viral RNA synthesis.
inhibition of initiation of RNA synthesis at the viral RNA polymerase
MOA
benzimidazole(HBB)
•Selectively inhibits many members of the Picornavirusgroup
•HBBdoes not interfere with early virus-cell interactions.
•It specificlyinhibits viral RNA synthesis
•But inhibition of viral polypeptide synthesis appears to be a
secondary effect due to inhibition of viral RNA synthesis.
inhibition of initiation of RNA synthesis at the viral RNA polymerase
MOA
4.Ribavirin(Virazole)
•Ribavirinis a guanosine(ribonucleic) analog
•After metabolized purineRNA nucleotides.
•Phosphorylatedto triphosphateby host enzymes, and inhibits
RNA-dependent RNA polymerase, viral RNA synthesis, and viral
replication
Ribavirin 5' mono- di- and tri-phosphates are all inhibitors of
viral RNA-dependent RNA polymerases which are essential to
the replication cycle of RNA viruses
viral hemorrhagic fevers including Lassa fever, Crimean-
Congo hemorrhagic fever, Venezuelan hemorrhagic fever,
and Hantavirus infection & FMD
MOA
•Ribavirinis a guanosine(ribonucleic) analog
•After metabolized purineRNA nucleotides.
•Phosphorylatedto triphosphateby host enzymes, and inhibits
RNA-dependent RNA polymerase, viral RNA synthesis, and viral
replication
Ribavirin 5' mono- di- and tri-phosphates are all inhibitors of
viral RNA-dependent RNA polymerases which are essential to
the replication cycle of RNA viruses
viral hemorrhagic fevers including Lassa fever, Crimean-
Congo hemorrhagic fever, Venezuelan hemorrhagic fever,
and Hantavirus infection & FMD
MOA
Ribavirin(Virazole)
•Brand name-
Side effects-
1.hemolytic anemia
2.Oxidative damage to erythrocyte cell membrane
3.Ribavirinis also a teratogen
Rebetol
Vilona
Videx
•Brand name-
Side effects-
1.hemolytic anemia
2.Oxidative damage to erythrocyte cell membrane
3.Ribavirinis also a teratogen
Rebetol
Vilona
Videx
5.Zidovudine(INN) or Azidothymidine(AZT)
•Nucleoside analog reverse-transcriptase inhibitor (NRTI)
•Jerome Horwitzof the Barbara Ann KarmanosCancer
Institute and Wayne State University, School of Medicine
first synthesized AZT in 1964
AZT is usually used in conjunction with the other anti-HIV
drugs in combination therapy called highly active
antiretroviral therapy (HAART).
➢The azidogroup increases the lipophilicnature allowing to cross the blood–
brain barrier
AZT works by selectively inhibiting viral
reverse transcriptase
Cellular enzymes convert AZT into the effective
5'-triphosphate form
•Nucleoside analog reverse-transcriptase inhibitor (NRTI)
•Jerome Horwitzof the Barbara Ann KarmanosCancer
Institute and Wayne State University, School of Medicine
first synthesized AZT in 1964
AZT is usually used in conjunction with the other anti-HIV
drugs in combination therapy called highly active
antiretroviral therapy (HAART).
➢The azidogroup increases the lipophilicnature allowing to cross the blood–
brain barrier
AZT works by selectively inhibiting viral
reverse transcriptase
Cellular enzymes convert AZT into the effective
5'-triphosphate form
•Brand name-
Retrovir
•Side effects
•Anemia, neutropenia, hepatotoxicity, cardiomyopathy, and
myopathy
Zidovudine(INN) or Azidothymidine(AZT)
Retrovir
•Side effects
•Anemia, neutropenia, hepatotoxicity, cardiomyopathy, and
myopathy
Zidovudine(INN) or Azidothymidine(AZT)
6.Dideoxycytidine/ Zalcitabine
•Nucleoside analog reverse transcriptase inhibitor (NARTI) under
the trade name Hivid.
•less potent than some other nucleoside RTIs
Zalcitabine is an analog of pyrimidine
It is phosphorylated in T cells and other HIV target cells
into its active triphosphate form
This works as a substrate for HIV reverse transcriptase and
incorporated into the viral DNA, hence terminating the
chain elongation due to the missing hydroxyl group
MOA
•Nucleoside analog reverse transcriptase inhibitor (NARTI) under
the trade name Hivid.
•less potent than some other nucleoside RTIs
Zalcitabine is an analog of pyrimidine
It is phosphorylated in T cells and other HIV target cells
into its active triphosphate form
This works as a substrate for HIV reverse transcriptase and
incorporated into the viral DNA, hence terminating the
chain elongation due to the missing hydroxyl group
MOA
•Side effects-
1.Peripheral neuropathy
2.Oral ulcers
3.Oesophageal ulcers
4.Pancreatitis
Dideoxycytidine/ Zalcitabine
1.Peripheral neuropathy
2.Oral ulcers
3.Oesophageal ulcers
4.Pancreatitis
Dideoxycytidine/ Zalcitabine
D
Drugs inhibiting virion-associated
enzymes and transcription
Drugs inhibiting virion-associated
enzymes and transcription
INHIBITORS OF TRANSCRIPTION
THYMIDINE KINASE DEPENDENT
PURINE ANALOGUES PYRIMIDINE ANALOGUES
ADININE GUANOSINE URIDINE THYMIDINE CYTOSINE
FOSCARNET
NON THYMIDINE KINASE DEPENDENT
VIDARABINE
ACYCLOVIR
GANCICLOVIR
PENCICLOVIR
IDOXURIDINEBRIVUDINE CYTARABINE
DRUG
MONOPHOSPHATE
FORM
TRIPHOSPHATE
FORM
COMPETE WITH
NATURAL
ANALOGUES
INCORPORATED
IN GROWING
CHAIN
PREMATURE
CHAIN
TERMINATION
VIRAL TK
CELLULAR KINASE
THYMIDINE KINASE DEPENDENT
PURINE ANALOGUES PYRIMIDINE ANALOGUES
ADININE GUANOSINE URIDINE THYMIDINE CYTOSINE
FOSCARNET
NON THYMIDINE KINASE DEPENDENT
VIDARABINE
ACYCLOVIR
GANCICLOVIR
PENCICLOVIR
IDOXURIDINEBRIVUDINE CYTARABINE
DRUG
MONOPHOSPHATE
FORM
TRIPHOSPHATE
FORM
COMPETE WITH
NATURAL
ANALOGUES
INCORPORATED
IN GROWING
CHAIN
PREMATURE
CHAIN
TERMINATION
VIRAL TK
CELLULAR KINASE
ACYCLOVIR
CHEMICAL NAME: ACYCLOGUANOSINE
✓Nucleosides isolated from a
Caribbean sponge Cryptotethya
crypta
TRADE NAME
Cyclovir, Herpex, Acivir, Acivirax,
Zovirax, Zoral, and Xovir.
INDICATIONS
• Herpes simplex virus type I (HSV-1)
• Herpes simplex virus type II (HSV-2)
• Varicella zoster virus (VZV)
• Epstein-Barr virus (EBV)
• Cytomegalovirus (CMV)
CHEMICAL NAME: ACYCLOGUANOSINE
✓Nucleosides isolated from a
Caribbean sponge Cryptotethya
crypta
TRADE NAME
Cyclovir, Herpex, Acivir, Acivirax,
Zovirax, Zoral, and Xovir.
INDICATIONS
• Herpes simplex virus type I (HSV-1)
• Herpes simplex virus type II (HSV-2)
• Varicella zoster virus (VZV)
• Epstein-Barr virus (EBV)
• Cytomegalovirus (CMV)
MECHANISM OF ACTION
ACV-GTP has 100 times
more affinity for viral
polymerase than host
polymerase
ACV-GTP incorporates
in growing DNA chain
by competing with host
guanosine
Premature chain
termination
ACV-GTP has 100 times
more affinity for viral
polymerase than host
polymerase
ACV-GTP incorporates
in growing DNA chain
by competing with host
guanosine
Premature chain
termination
SIDE EFFECTS
Nausea, Vomiting, Diarrhea, Headache.
At high doses: Sore throat, Agitation, Vertigo , Leucopenia.
Resistance
Mechanisms of resistance in HSV include
• Deficient viral thymidine kinase
• Mutations : viral thymidine kinase and/or DNA polymerase
Nausea, Vomiting, Diarrhea, Headache.
At high doses: Sore throat, Agitation, Vertigo , Leucopenia.
Resistance
Mechanisms of resistance in HSV include
• Deficient viral thymidine kinase
• Mutations : viral thymidine kinase and/or DNA polymerase
DRUG ANALOGUE TRADE NAME INDICATIONS
VIDARABINE ADENINE VIRA-A HERPES ,POX,
HEPADNA,
RHABDO
GANCICLOVIR GUANOSINE CYTOVENE CMV ( 1
st
drug
approved against
CMV)
FAMCICLOVIR GUANOSINE FAMVIR ZOSTER,
GENITAL HERPES
IDOXURIDINE URIDINE HERPES SIMPLEX
KERATITIS
BRIVUDINE THYMIDINE BRIVIX VARICELLA -
ZOSTER
CYTARABINE CYTOSINE CYTOSAR-V MYLEOID
LEUKEMIA
FOSCARNET FOSCAVIR HSV,VZV, HCMV
VIDARABINE ADENINE VIRA-A HERPES ,POX,
HEPADNA,
RHABDO
GANCICLOVIR GUANOSINE CYTOVENE CMV ( 1
st
drug
approved against
CMV)
FAMCICLOVIR GUANOSINE FAMVIR ZOSTER,
GENITAL HERPES
IDOXURIDINE URIDINE HERPES SIMPLEX
KERATITIS
BRIVUDINE THYMIDINE BRIVIX VARICELLA -
ZOSTER
CYTARABINE CYTOSINE CYTOSAR-V MYLEOID
LEUKEMIA
FOSCARNET FOSCAVIR HSV,VZV, HCMV
•RTIs are a class of anti-retroviral drugs used to treat HIV/AIDS.
•RTIs inhibit activity of reverse transcriptase
Reverse-transcriptase inhibitors (RTIs)
Reverse transcriptase
Viral RNA
Proviral DNA
INTEGRATED IN HOST GENOME
RTIs block reverse transcriptase's enzymatic function and prevent
completion of synthesis of the double-stranded viral DNA
RTIs used for blocking HEPATITS –B Replication as these viruses
use RNA Dependent RNA Polymerase for their replication
•RTIs inhibit activity of reverse transcriptase
Reverse-transcriptase inhibitors (RTIs)
Reverse transcriptase
Viral RNA
Proviral DNA
INTEGRATED IN HOST GENOME
RTIs block reverse transcriptase's enzymatic function and prevent
completion of synthesis of the double-stranded viral DNA
RTIs used for blocking HEPATITS –B Replication as these viruses
use RNA Dependent RNA Polymerase for their replication
RTIs TYPES:
analogues of the naturally occurring
deoxynucleotides needed to synthesize the
viral DNA
compete with the natural deoxynucleotides for
incorporation into the growing viral DNA chain.
incorporated into forming DNA
cannot form 5'-3' phosphodiester bond as they
lack 3’hydroxyl group
no elongation of chain
chain termination
block reverse transcriptase by
binding at a different site on the
enzyme.
NNRTIs are not incorporated into
the viral DNA
inhibit the movement of protein
domains of reverse transcriptase
that are needed to carry out the
process of DNA synthesis
Nucleoside analog
reverse-transcriptase
inhibitors (NARTIs or
NRTIs)
• Nucleotide analog
reverse-transcriptase
inhibitors (NtARTIs or
NtRTIs)
• Non-nucleoside
reverse-transcriptase
inhibitors (NNRTIs)
analogues of the naturally occurring
deoxynucleotides needed to synthesize the
viral DNA
compete with the natural deoxynucleotides for
incorporation into the growing viral DNA chain.
incorporated into forming DNA
cannot form 5'-3' phosphodiester bond as they
lack 3’hydroxyl group
no elongation of chain
chain termination
block reverse transcriptase by
binding at a different site on the
enzyme.
NNRTIs are not incorporated into
the viral DNA
inhibit the movement of protein
domains of reverse transcriptase
that are needed to carry out the
process of DNA synthesis
Nucleoside analog
reverse-transcriptase
inhibitors (NARTIs or
NRTIs)
• Nucleotide analog
reverse-transcriptase
inhibitors (NtARTIs or
NtRTIs)
• Non-nucleoside
reverse-transcriptase
inhibitors (NNRTIs)
Nucleoside analog reverse-transcriptase inhibitors (NARTIs or NRTIs)
Zidovudine Also called azidothymidine
Mechanism Of Action
Compete with thymidine
Incorporate in Elongating
chain
Chain termination
Zidovudine Also called azidothymidine
Mechanism Of Action
Compete with thymidine
Incorporate in Elongating
chain
Chain termination
Used for treatment of HIV/AIDS
AZT slows replication cycle in patient but do not stop entirely.
So AZT is used in combination with other retroviral drugs called
HARRT (Highly Active Retroviral Therapy)
Side effects:
Anemia, neutropenia , hepatotoxicity, Cardiomyopathy.
Resistance:
Mainly by mutation in Reverse Transcriptase
Zidovudine
FDA approved this drug on 20 march 1987
First U.S. Govt. approved therapy for HIV
AZT slows replication cycle in patient but do not stop entirely.
So AZT is used in combination with other retroviral drugs called
HARRT (Highly Active Retroviral Therapy)
Side effects:
Anemia, neutropenia , hepatotoxicity, Cardiomyopathy.
Resistance:
Mainly by mutation in Reverse Transcriptase
Zidovudine
FDA approved this drug on 20 march 1987
First U.S. Govt. approved therapy for HIV
OTHER NARTIs or NRTIs
Didanosine(adenosine) Videx
Zalcitabine(deoxycytidine) Hivid
Stavudine Zerit
Lamivudine Zeffix
Abacavir(guanosine) Ziagen
Emtricitabine Emtriva
Entecavir Baraclude
DRUGS TRADE NAME
Didanosine(adenosine) Videx
Zalcitabine(deoxycytidine) Hivid
Stavudine Zerit
Lamivudine Zeffix
Abacavir(guanosine) Ziagen
Emtricitabine Emtriva
Entecavir Baraclude
DRUGS TRADE NAME
Nucleotide analog reverse-transcriptase inhibitors (NtARTIs or NtRTIs)
Ordinary DNA
Replication
molecules
incorporated DNA replication
cannot continue
Tenofovir
TENOFOVIR
Mechanism Of Action
Tenofovir is a nucleotide analogue
Directly incorporated
No phosphorylation as in case of nucleoside inhibitors
Ordinary DNA
Replication
molecules
incorporated DNA replication
cannot continue
Tenofovir
TENOFOVIR
Mechanism Of Action
Tenofovir is a nucleotide analogue
Directly incorporated
No phosphorylation as in case of nucleoside inhibitors
TENOFOVIR
Trade name : Virad
Indications:
HIV, Hepatitis-B
Side Effects:
Vomitting, Diarrohea, Asthesia, Fanconi Syndrome
Approved by FDA : 2001 – HIV
2008- Hepatitis -B
Adefovir:
Trade name: Preveon and Hepsera.
Dissaproved by FDA due to high toxicity
Trade name : Virad
Indications:
HIV, Hepatitis-B
Side Effects:
Vomitting, Diarrohea, Asthesia, Fanconi Syndrome
Approved by FDA : 2001 – HIV
2008- Hepatitis -B
Adefovir:
Trade name: Preveon and Hepsera.
Dissaproved by FDA due to high toxicity
Non-nucleoside reverse-transcriptase inhibitors (NNRTIs)
ETRAVIRINE
Etravirine is adiarylpyrimidine (DAPY), with conformational
isomerism that bind the enzymereverse transcriptase in
multiple conformations
Inhibit movement of protein
domains of RT that carry out
DNA synthesis
No DNA replication
Bind at a different site on RT
Mechanism Of Action
ETRAVIRINE
Etravirine is adiarylpyrimidine (DAPY), with conformational
isomerism that bind the enzymereverse transcriptase in
multiple conformations
Inhibit movement of protein
domains of RT that carry out
DNA synthesis
No DNA replication
Bind at a different site on RT
Mechanism Of Action
ETRAVIRINE
Side effects:
Hypersensitivity , Hepatic toxicity
Trade name:
Tibotec
FDA approved this drug in 2008
OTHER Non-nucleoside reverse-transcriptase inhibitors (NNRTIs)
DRUG TRADE NAME
Efavirenz Sustiva and Stocrin
Nevirapine Viramune
Delavirdine Rescriptor
Rilpivirine Edurant
Side effects:
Hypersensitivity , Hepatic toxicity
Trade name:
Tibotec
FDA approved this drug in 2008
OTHER Non-nucleoside reverse-transcriptase inhibitors (NNRTIs)
DRUG TRADE NAME
Efavirenz Sustiva and Stocrin
Nevirapine Viramune
Delavirdine Rescriptor
Rilpivirine Edurant
Antiretroviral Drugs
Current classes of antiretroviral drugs
Three main enzymatic targets:
Reverse Transcriptase,
Protease,
Integrase
Six drug classes :-
1.Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
2.Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
3.Protease inhibitors (PIs)
4.Integrase inhibitors
5.Entry inhibitors
6.CCR5/CXCR4 receptor antagonists
Three main enzymatic targets:
Reverse Transcriptase,
Protease,
Integrase
Six drug classes :-
1.Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
2.Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
3.Protease inhibitors (PIs)
4.Integrase inhibitors
5.Entry inhibitors
6.CCR5/CXCR4 receptor antagonists
ViralR
NA
double helix
DNA
Incorporated
into host
genome
Reverse
transcriptase
Integrase
transcription
translation
Polyproteins
Final
structural
proteins
Protease
Drugs
NRTIs
NNRTIs
PIs
Integrase Inhibitor
NA
double helix
DNA
Incorporated
into host
genome
Reverse
transcriptase
Integrase
transcription
translation
Polyproteins
Final
structural
proteins
Protease
Drugs
NRTIs
NNRTIs
PIs
Integrase Inhibitor
Current ARV Drugs
NRTI
•Zidovudine
•Didanosine
•Zalcitabine
•Stavudine
•Tenofovir
•Abacavir
•Emtricitabine
(FTC)
•Lamivudine
(3TC)
PI
•Atazanavir
•Indinavir
•Lopinavir
•Nelfinavir
•Ritonavir
•Saquinavir
•Amprenavir
•Darunavir
•Fosamprenavir
NNRTI
•Efavirenz
•Etravirine
•Nevirapine
•Cabenuva
•Cabotegravir
•Rilpivirine
•Delavirdine
•Dolutegravir
•Doravirine
•Edurant
Integrase
Inhibitor
•Raltegravir
•Bictegravir
•Dolutegravir
•Elvitegravir
•Isentress
•Dofetilide
•Triumeq
NRTI
•Zidovudine
•Didanosine
•Zalcitabine
•Stavudine
•Tenofovir
•Abacavir
•Emtricitabine
(FTC)
•Lamivudine
(3TC)
PI
•Atazanavir
•Indinavir
•Lopinavir
•Nelfinavir
•Ritonavir
•Saquinavir
•Amprenavir
•Darunavir
•Fosamprenavir
NNRTI
•Efavirenz
•Etravirine
•Nevirapine
•Cabenuva
•Cabotegravir
•Rilpivirine
•Delavirdine
•Dolutegravir
•Doravirine
•Edurant
Integrase
Inhibitor
•Raltegravir
•Bictegravir
•Dolutegravir
•Elvitegravir
•Isentress
•Dofetilide
•Triumeq
Actbycompetitiveinhibitionofreversetranscriptase;
incorporationintothegrowingviralDNAchainresults
inprematurechainterminationduetoinhibitionof
bindingwiththeincomingnucleotide.
Requireintracytoplasmicactivationviaphosphorylation
bycellularenzymestothetriphosphateform.
Mechanism of Action of NRTIS
incorporationintothegrowingviralDNAchainresults
inprematurechainterminationduetoinhibitionof
bindingwiththeincomingnucleotide.
Requireintracytoplasmicactivationviaphosphorylation
bycellularenzymestothetriphosphateform.
Mechanism of Action of NRTIS
❖Mechanism of Action
PPPP PP
NRTI NRTIp NRTIpp NRTIppp
(dNTP)
(RNA/DNAË«Á´)
PPP
PPP
OOOOOOO
DNA
OOOOOOOO
RNA
(NRTIP3)
PPPP PP
NRTI NRTIp NRTIpp NRTIppp
(dNTP)
(RNA/DNAË«Á´)
PPP
PPP
OOOOOOO
DNA
OOOOOOOO
RNA
(NRTIP3)
3`-Azido-2`,3`-
dideoxythymidine
Zidovudine (AZT)
✓ Deoxythymidine analog
✓ anti-HIV-1 and HIV-2
✓ Well absorbed from the gut and distributed to most body
tissues and fluids, including the cerebrospinal fluid
✓. Adverse effect: myelosuppression,anemia or neutropenia;
gastrointestinal intolerance, headachs, insomnia
dideoxythymidine
Zidovudine (AZT)
✓ Deoxythymidine analog
✓ anti-HIV-1 and HIV-2
✓ Well absorbed from the gut and distributed to most body
tissues and fluids, including the cerebrospinal fluid
✓. Adverse effect: myelosuppression,anemia or neutropenia;
gastrointestinal intolerance, headachs, insomnia
Zalcitabine
•Cytosine analog
•Anti-HIV-1
•Zalcitabine + Zidovudine + one protease inhibitor
•Long intracellular half-life of 10hr.
•Dose-dependent peripheral neuropathy.
Contraindication to use with other drugs that may
cause neuropathy.
•Cytosine analog
•Anti-HIV-1
•Zalcitabine + Zidovudine + one protease inhibitor
•Long intracellular half-life of 10hr.
•Dose-dependent peripheral neuropathy.
Contraindication to use with other drugs that may
cause neuropathy.
Stavudine
•Thymidine analog
•Not used with AZT because AZT may reduce the
phosphorylation of Stavudine.
•Anti-HIV-1 and HIV-2
•High oral bioavailability(86%) that is not food-
dependent.
•Adverse effect:-
peripheral neuropathy, pancreatitis
•Thymidine analog
•Not used with AZT because AZT may reduce the
phosphorylation of Stavudine.
•Anti-HIV-1 and HIV-2
•High oral bioavailability(86%) that is not food-
dependent.
•Adverse effect:-
peripheral neuropathy, pancreatitis
Non nucleoside reverse transcriptase
inhibitors(NNRTIs)
oIncludes:-Delavirdine,Nevirapine,Efavirenz
MOA:-
•Binddirectlytoasiteontheviralreverse
transcriptasethatisneartobutdistinctfromthe
bindingsiteoftheNRTIs.
•Neithercompetewithnucleosidetriphosphatesnor
requirephosphorylationtobeactive.
•Thebindingtotheenzyme’sactivesiteresultsin
blockadeofRNA-andDNA-dependentDNA
polymeraseactivities.
inhibitors(NNRTIs)
oIncludes:-Delavirdine,Nevirapine,Efavirenz
MOA:-
•Binddirectlytoasiteontheviralreverse
transcriptasethatisneartobutdistinctfromthe
bindingsiteoftheNRTIs.
•Neithercompetewithnucleosidetriphosphatesnor
requirephosphorylationtobeactive.
•Thebindingtotheenzyme’sactivesiteresultsin
blockadeofRNA-andDNA-dependentDNA
polymeraseactivities.
Protease inhibitors
•Including ritonavir, nelfinavir, saquinavir, indinavirand
amprenavir.
Gag and Gag-Pol
gene
Polyproteins,
Immature budding particles
translate
Final structural proteins,
Mature virion core
Viral protease
✓By inhibiting protease the drugs block the maturation of the virus
✓Viral protease is an endopeptidase that cleaves viral polypeptide products
to form structural proteins of the virion core and essential viral enzymes (i.e
reverse transcriptase, integrase, etc.)
•Including ritonavir, nelfinavir, saquinavir, indinavirand
amprenavir.
Gag and Gag-Pol
gene
Polyproteins,
Immature budding particles
translate
Final structural proteins,
Mature virion core
Viral protease
✓By inhibiting protease the drugs block the maturation of the virus
✓Viral protease is an endopeptidase that cleaves viral polypeptide products
to form structural proteins of the virion core and essential viral enzymes (i.e
reverse transcriptase, integrase, etc.)
Protease Inhibitors:-Side Effects
•Metabolic Disorders
–Hepatotoxicity
–Hyperglycemia, insulin resistance
–Lipid abnormalities (increases in triglyceride and LDL
levels)
–Fat redistribution
•Bone Disorders
•GI Intolerance
•Metabolic Disorders
–Hepatotoxicity
–Hyperglycemia, insulin resistance
–Lipid abnormalities (increases in triglyceride and LDL
levels)
–Fat redistribution
•Bone Disorders
•GI Intolerance
Integrase Inhibitor
•Raltegravir(Isentress, IsentressHD)
•Bictegravir(Bictarvy)
•Dolutegravir (DTG)
•Elvitegravir (EVG)
•Part of HAART
MOA:IntegraseinhibitorsdependononthefactthatHIV
needsintegrasetoreplicate.
ThesedrugsstopHIVfrombeingintegrationintohost
genome.
Withoutintegraseenzyme,HIVcan’ttakeoverCD4cellsto
copyitselfandtheHIVlifecycleisinterrupted.
•Raltegravir(Isentress, IsentressHD)
•Bictegravir(Bictarvy)
•Dolutegravir (DTG)
•Elvitegravir (EVG)
•Part of HAART
MOA:IntegraseinhibitorsdependononthefactthatHIV
needsintegrasetoreplicate.
ThesedrugsstopHIVfrombeingintegrationintohost
genome.
Withoutintegraseenzyme,HIVcan’ttakeoverCD4cellsto
copyitselfandtheHIVlifecycleisinterrupted.
Antiretroviral (ARV) Drug Regimens
Always combine multiple agents.
Usually 2 NRTIs along with:
A PI enhanced with a low dose of a second PI,
An NNRTI
An integrase inhibitor
An entry inhibitor
HAART-Highly Active Anti-Retroviral Therapy
Taking3ormoreantiretroviraldrugsatthesametimevastlyreducesthe
rateatwhichresistancedevelops,theapproachisknownashighly
activeantiretroviraltherapy,orHAART.
Always combine multiple agents.
Usually 2 NRTIs along with:
A PI enhanced with a low dose of a second PI,
An NNRTI
An integrase inhibitor
An entry inhibitor
HAART-Highly Active Anti-Retroviral Therapy
Taking3ormoreantiretroviraldrugsatthesametimevastlyreducesthe
rateatwhichresistancedevelops,theapproachisknownashighly
activeantiretroviraltherapy,orHAART.
INTERFERON:
Classification, Production & Antiviral Activity
Classification, Production & Antiviral Activity
➢DiscoveredbyIsaacs&Lindenmanin
1957.
➢Interferonsplayanimportantrolein
thefirstlineofdefenseagainstviral
infections.
➢Interferonsarepartofthenon-specific
immunesystem.
➢Interferonsaremadebycellsin
responsetoanappropriatestimulus.
Introduction
1957.
➢Interferonsplayanimportantrolein
thefirstlineofdefenseagainstviral
infections.
➢Interferonsarepartofthenon-specific
immunesystem.
➢Interferonsaremadebycellsin
responsetoanappropriatestimulus.
Introduction
TYPES OF INTERFERON
➢IFN α (leukocyte interferon)
–produced by virus infected leukocytes
➢IFN β (fibroblast interferon)
–produced by virus infected fibroblasts or
epithelial cells
➢IFN γ(immune interferon)
–produced by certain activated T cells & NK
cells
Types of interferon
TYPE I interferon TYPE II inteferon
INFα INFβ INFγ
(Viral
Interferon)
Immune
Interferon
➢IFN α (leukocyte interferon)
–produced by virus infected leukocytes
➢IFN β (fibroblast interferon)
–produced by virus infected fibroblasts or
epithelial cells
➢IFN γ(immune interferon)
–produced by certain activated T cells & NK
cells
Types of interferon
TYPE I interferon TYPE II inteferon
INFα INFβ INFγ
(Viral
Interferon)
Immune
Interferon
virus
cells
(Other stimuli:
exogenous ds RNA,
LPS, bacterial
components)
How Does It Prevent Viral Replication?
cells
(Other stimuli:
exogenous ds RNA,
LPS, bacterial
components)
How Does It Prevent Viral Replication?
virus
interferon
How Does It Prevent Viral Replication?
interferon
How Does It Prevent Viral Replication?
virus
Inhibitory
proteins
No replication
How Does It Prevent Viral Replication?
Inhibitory
proteins
No replication
How Does It Prevent Viral Replication?
IFN System
Mechanism Of Action
IFN-Induced Gene Products and Their Antiviral Actions
Ds RNA –activated
protein kinase
Mxproteins.
RNase L and 2′-5′-
oligo(A) synthetase
Nitric oxide
synthase
Interferon
regulatory proteins
Promyelocytic
leukemia proteins
Ubiquitin-
proteasome
pathway
components
Cellular micro-
RNAs
Ds RNA –activated
protein kinase
Mxproteins.
RNase L and 2′-5′-
oligo(A) synthetase
Nitric oxide
synthase
Interferon
regulatory proteins
Promyelocytic
leukemia proteins
Ubiquitin-
proteasome
pathway
components
Cellular micro-
RNAs
Antiviral Action Of Interferon Induced Proteins
1.Membersoftheirfgenefamily(irf2–irf9)boundtotheISRE
inpromotersofIFNregulatedgenes.
2.Pmlproteinsarepresentinnucleoplasm&discrete
multiproteincomplexes.TheybindforeignDNAthatenters
nucleus&exertantiviraldefensebynucleosomeremodelling
&transcriptionalrepression.
3.Hostmi-RNAplaycentralroleinshuttingdownHIVtype-I
transcriptioninbloodmononuclearcellsfrominfected
doners.
Antiviral Effects of Irf,PmlProtein & mi RNAs
inpromotersofIFNregulatedgenes.
2.Pmlproteinsarepresentinnucleoplasm&discrete
multiproteincomplexes.TheybindforeignDNAthatenters
nucleus&exertantiviraldefensebynucleosomeremodelling
&transcriptionalrepression.
3.Hostmi-RNAplaycentralroleinshuttingdownHIVtype-I
transcriptioninbloodmononuclearcellsfrominfected
doners.
Antiviral Effects of Irf,PmlProtein & mi RNAs
Viral Products Inhibiting IFN Response
Viral Products Inhibiting IFN Response
Recombinant Production Of IFN
Restriction enzymes cut
the plasmid open
E.Coli containing its
own chromosome
Plasmid
Human Fibroblast
Human Interferon beta
gene
Modified human
interferon beta gene
R-DNA
E.Coli containing R-DNA
Replicated E.Coli producing
interferon beta-1b
Purified interferon
beta 1-b The end product
The Manufacture of Betaferon
Restriction enzymes cut
the plasmid open
E.Coli containing its
own chromosome
Plasmid
Human Fibroblast
Human Interferon beta
gene
Modified human
interferon beta gene
R-DNA
E.Coli containing R-DNA
Replicated E.Coli producing
interferon beta-1b
Purified interferon
beta 1-b The end product
The Manufacture of Betaferon
Agent Nature of AgentClinical Application
Roferon Interferon alpha 2-aHepatistisB,
Hairy cell Leukemia,
Kaposi’s Sarcoma
IntronA Interferon alpha 2-bHepatistisC
Melanoma
Betaseron Interferon β-1b Multiple Sclerosis
Avonex Interferon β-1a Multiple Sclerosis
Actimmune Interferonγ-1β Chronic
Granulomatous
Disease(CGD)
Osteopetrosis
IFN Therapy
Roferon Interferon alpha 2-aHepatistisB,
Hairy cell Leukemia,
Kaposi’s Sarcoma
IntronA Interferon alpha 2-bHepatistisC
Melanoma
Betaseron Interferon β-1b Multiple Sclerosis
Avonex Interferon β-1a Multiple Sclerosis
Actimmune Interferonγ-1β Chronic
Granulomatous
Disease(CGD)
Osteopetrosis
IFN Therapy
FDA
APPROVED
REGULAR PEGYLATED
ALFA BETA GAMMA ALFA - 2a ALFA - 2b
2 a
2 b
ROFERON A
INTRON A
PEGASYS PEGINTRON
gamma-1b
Actimmune
Beta-1a
Avonex
Beta-1b
Betaseron
ALFA-N3
ALFACON 1
ALFERON N
INFERGEN
APPROVED
REGULAR PEGYLATED
ALFA BETA GAMMA ALFA - 2a ALFA - 2b
2 a
2 b
ROFERON A
INTRON A
PEGASYS PEGINTRON
gamma-1b
Actimmune
Beta-1a
Avonex
Beta-1b
Betaseron
ALFA-N3
ALFACON 1
ALFERON N
INFERGEN
Pegylation
➢Process of covalent attachment of
(polyethylene glycol) polymer
chains to drug or therapeutic protein.
➢It produces alterations in the
physiochemical properties including
changes in confirmation,
electrostatic binding, hydrophobicity
etc.
➢These physical and chemical
changes increase systemic retention
of the therapeutic agent.
➢It can influence the binding affinity
of the therapeutic moiety to the cell
receptors and can alter the
absorption and distribution patterns
➢Process of covalent attachment of
(polyethylene glycol) polymer
chains to drug or therapeutic protein.
➢It produces alterations in the
physiochemical properties including
changes in confirmation,
electrostatic binding, hydrophobicity
etc.
➢These physical and chemical
changes increase systemic retention
of the therapeutic agent.
➢It can influence the binding affinity
of the therapeutic moiety to the cell
receptors and can alter the
absorption and distribution patterns
Nucleic acid–based
antiviral
therapeutics
Sidney Altman Tom Cech
1989 Nobel Prize
In Chemistry for ‘catalytic properties of RNA’
Latest Trends in Antiviral Drug Development
antiviral
therapeutics
Sidney Altman Tom Cech
1989 Nobel Prize
In Chemistry for ‘catalytic properties of RNA’
Latest Trends in Antiviral Drug Development
Introduction
❖Nucleic Acid based antivirals are highly specific and relatively easy to
produce
❖Don’t rely on disruption of active metabolism
❖Involves targeting of specific nucleotides rather than proteins.
❖Could allow targeting of even latent viruses
Nucleic acid
based antiviral
therapeutics
Antisense
Oligonucleotides
DNAzymes Ribozymes siRNA/miRNA
❖Nucleic Acid based antivirals are highly specific and relatively easy to
produce
❖Don’t rely on disruption of active metabolism
❖Involves targeting of specific nucleotides rather than proteins.
❖Could allow targeting of even latent viruses
Nucleic acid
based antiviral
therapeutics
Antisense
Oligonucleotides
DNAzymes Ribozymes siRNA/miRNA
Antisense Oligonucleotidestarget mRNA
antisense ODN
Normal Protein Production Antisense Inhibition
DNA
DNA
Antisense Oligonucleotide
mRNA
Protein
NoProtein
Production
mRNA
5’…-A-G-G-U-C-A-C-U-U-U-G-C-A-A-C-G-…3’
••••••••••••
3’-C-A-G-T-G-A-A-A-C-G-T-T-5’
antisense ODN
Normal Protein Production Antisense Inhibition
DNA
DNA
Antisense Oligonucleotide
mRNA
Protein
NoProtein
Production
mRNA
5’…-A-G-G-U-C-A-C-U-U-U-G-C-A-A-C-G-…3’
••••••••••••
3’-C-A-G-T-G-A-A-A-C-G-T-T-5’
Antisense Oligonucleotides
May be:
•Synthetic and introduced from out side the cell or
•May be introduced from expression vectors
Three
Approaches
Antisense
inhibition
Antigène
inhibition
Decoy
oligonuclé
otides
May be:
•Synthetic and introduced from out side the cell or
•May be introduced from expression vectors
Three
Approaches
Antisense
inhibition
Antigène
inhibition
Decoy
oligonuclé
otides
Antisense Oligonucleotides
Down-regulation duration depends on ODN backbone structure
and its susceptibility to nuclease degradation.
PO ODN
•Rapidly degraded by cellular nucleases
•Transitory effects. BASE
HO
BASE
O
O
O
O
O
O
P
O
SUGAR
BASE
HO
BASEBASE
O
O
O
O
O
O
P
O
SUGAR BASE
HO
BASE
O
O
O
O
O
O
P
O
SUGAR
BASE
HO
BASEBASE
O
O
O
O
O
O
P
O
SUGAR
S
PS ODN (Phosphorothioate)
•Less susceptible to nuclease attack
•Longer lasting down-regulation
Down-regulation duration depends on ODN backbone structure
and its susceptibility to nuclease degradation.
PO ODN
•Rapidly degraded by cellular nucleases
•Transitory effects. BASE
HO
BASE
O
O
O
O
O
O
P
O
SUGAR
BASE
HO
BASEBASE
O
O
O
O
O
O
P
O
SUGAR BASE
HO
BASE
O
O
O
O
O
O
P
O
SUGAR
BASE
HO
BASEBASE
O
O
O
O
O
O
P
O
SUGAR
S
PS ODN (Phosphorothioate)
•Less susceptible to nuclease attack
•Longer lasting down-regulation
Common chemical modifications used for Antisense
Oligonucleotides
Oligonucleotides
DNAzymes
Santoro and Joyce evolved highly efficient magnesium-dependent DNAzymes
capable of cleaving all RNA substrates
Both containing a conserved catalytic domain flanked by two variable binding-
domains that provide target specificity through Watson-Crick base pairing.
Two
prototypes
8-17
RNA cleaving
DNAzymes
10-23
RNA cleaving
DNAzymes
Santoro and Joyce, 1997
Santoro and Joyce evolved highly efficient magnesium-dependent DNAzymes
capable of cleaving all RNA substrates
Both containing a conserved catalytic domain flanked by two variable binding-
domains that provide target specificity through Watson-Crick base pairing.
Two
prototypes
8-17
RNA cleaving
DNAzymes
10-23
RNA cleaving
DNAzymes
Santoro and Joyce, 1997
DNAzymes (MOA)
•Specific DNAzymes were
designed for specific cleavage
of some conservative regions or
the expression of some key
genes in the virus genome.
•The DNAzyme can be directed
to the cleavage site by
designing the substrate
binding arms using Watson-
Crick base pairing, thus
inhibiting gene expression.
•These DNAzymes has good
cleavage efficiency in vitro,
effectively inhibiting the
occurrence and spread of the
virus.
•Specific DNAzymes were
designed for specific cleavage
of some conservative regions or
the expression of some key
genes in the virus genome.
•The DNAzyme can be directed
to the cleavage site by
designing the substrate
binding arms using Watson-
Crick base pairing, thus
inhibiting gene expression.
•These DNAzymes has good
cleavage efficiency in vitro,
effectively inhibiting the
occurrence and spread of the
virus.
DNAzymes
The specificity of DNAzymes was one of the concerns to arise.
Because of their impressive catalytic properties, any off-target
cleavage could be potentially disastrous.
Modifications to the:
✓Phosphate backbone
✓Ribose sugar moiety
✓to the oligonucleotide structure
Endow DNAzymes with properties to avoid nuclease digestion
Finding the sites which are amenable to efficient hybridisation
and cleavage is usually a difficult and time consuming task
The specificity of DNAzymes was one of the concerns to arise.
Because of their impressive catalytic properties, any off-target
cleavage could be potentially disastrous.
Modifications to the:
✓Phosphate backbone
✓Ribose sugar moiety
✓to the oligonucleotide structure
Endow DNAzymes with properties to avoid nuclease digestion
Finding the sites which are amenable to efficient hybridisation
and cleavage is usually a difficult and time consuming task
Ribozymes
Ribonucleic
acid
Enzyme Ribozyme
✓RNA only enzymes
✓Capable of cutting RNA molecules at
specific without the need of proteins
✓First described in protozoan
Tetrahymenia
✓Cleavage occurs at precise sequence
✓Design synthetic ribozymes that cut
at a sequence specific for a target
virus
✓Large molecules posing significant
problems of delivery
Ribonucleic
acid
Enzyme Ribozyme
✓RNA only enzymes
✓Capable of cutting RNA molecules at
specific without the need of proteins
✓First described in protozoan
Tetrahymenia
✓Cleavage occurs at precise sequence
✓Design synthetic ribozymes that cut
at a sequence specific for a target
virus
✓Large molecules posing significant
problems of delivery
Ribozymes
Classification
Hammerhead
Ribozyme
(Plant Virus)
Hairpin
Ribozyme
(Plant Virus)
Hepatitis delta
ribozyme
(human virus)
Group I and
group II
introns
RNA subunit
of RNaseP
Classification
Hammerhead
Ribozyme
(Plant Virus)
Hairpin
Ribozyme
(Plant Virus)
Hepatitis delta
ribozyme
(human virus)
Group I and
group II
introns
RNA subunit
of RNaseP
Hammerhead Ribozyme
The hammerhead ribozyme currently holds much of the hope for the use of ribozyme
technology in the inhibition of virus replication, modulation of tumour progression
and analysis of cellular gene function.
The hammerhead ribozyme consists of
three basic components:
✓A highly conserved 22-
nucleotide catalytic domain
✓Substrate-binding sequences
that flank the susceptible 3´,5´
phosphodiester bond
✓A recognition sequence on the
target RNA
Ribozymes are generally less stable, more susceptible to off-target catalysis,
and the overall kinetic efficiency of cleavage is generally slower.
The hammerhead ribozyme currently holds much of the hope for the use of ribozyme
technology in the inhibition of virus replication, modulation of tumour progression
and analysis of cellular gene function.
The hammerhead ribozyme consists of
three basic components:
✓A highly conserved 22-
nucleotide catalytic domain
✓Substrate-binding sequences
that flank the susceptible 3´,5´
phosphodiester bond
✓A recognition sequence on the
target RNA
Ribozymes are generally less stable, more susceptible to off-target catalysis,
and the overall kinetic efficiency of cleavage is generally slower.
A cellular nuclease binds to the dsRNA cleaving it into ssRNAs of 21-23 nucleotides each.
The nuclease-RNA oligonucleotide complex binds and cleaves specific mRNA.
dsRNA
Binding of dsRNA-specific nuclease
cleavage
mRNA is cleaved
Nuclease-ssRNA complex
Hybridizes to mRNA
sense
antisense
RNA interference (RNAi)
The nuclease-RNA oligonucleotide complex binds and cleaves specific mRNA.
dsRNA
Binding of dsRNA-specific nuclease
cleavage
mRNA is cleaved
Nuclease-ssRNA complex
Hybridizes to mRNA
sense
antisense
RNA interference (RNAi)
siRNA/miRNA
•Short interfering RNAs (siRNAs)
and microRNAs (miRNAs)—act in
both somatic and germline line to
regulate endogenous genes and to
defend the genome from invasive
nucleic acids.
•siRNA are highly specific with
single target site in a single
mRNA, and, therefore, inhibits the
expression of one target gene,
whereas miRNA have multiple
targets
•siRNAs shut down gene
expression at a post-transcriptional
level through mRNA degradation,
while miRNAs silence their target
genes mainly through translational
repression
•Short interfering RNAs (siRNAs)
and microRNAs (miRNAs)—act in
both somatic and germline line to
regulate endogenous genes and to
defend the genome from invasive
nucleic acids.
•siRNA are highly specific with
single target site in a single
mRNA, and, therefore, inhibits the
expression of one target gene,
whereas miRNA have multiple
targets
•siRNAs shut down gene
expression at a post-transcriptional
level through mRNA degradation,
while miRNAs silence their target
genes mainly through translational
repression
Miravirsen is a LNA modified phosphorothiolate antisense oligonucleotide targeting and
blocking miR-122
Locked nucleic acid (LNA) – modified oligonucleotides
are anti-miRNAs with a 2′ sugar modification in which the
ribose is locked in a C3′-endo conformation by a 2′-O, 4′-C
methylene bridge that strongly increases the affinity for
complementary RNA and increases the duplex melting
temperature
blocking miR-122
Locked nucleic acid (LNA) – modified oligonucleotides
are anti-miRNAs with a 2′ sugar modification in which the
ribose is locked in a C3′-endo conformation by a 2′-O, 4′-C
methylene bridge that strongly increases the affinity for
complementary RNA and increases the duplex melting
temperature
Miravirsen- the 1
st
miRNA targeted drug
✓First drug to exploit miRNA for therapeutic use
✓As a host targeting agent miravirsen poses a high barrier to resistance
✓Can work in all HCV genotypes because miR-122 binding sites are conserved
✓Has successfully completed Phase II clinical trial
st
miRNA targeted drug
✓First drug to exploit miRNA for therapeutic use
✓As a host targeting agent miravirsen poses a high barrier to resistance
✓Can work in all HCV genotypes because miR-122 binding sites are conserved
✓Has successfully completed Phase II clinical trial
Nucleic acid–based antiviral therapeutics that have entered clinical
trials
Nature, 2008
Fomivirsin
✓Approved for CMV
retinitis
✓Antisense ODN
stabilized with
phosphorothiolate
modification
trials
Nature, 2008
Fomivirsin
✓Approved for CMV
retinitis
✓Antisense ODN
stabilized with
phosphorothiolate
modification
Newly Emerging Strategies in Antiviral Drug Discovery
Proteolysis Targeting Chimera (PROTAC)
•Emerging drug discovery platform
•Promoting and recognizing the degradation of target proteins via the ubiquitin–
proteasome system (UPS)
•PROTACs are hetero-bifunctional molecules consisting of a ligand for the protein of
interest (POI), an E3 ubiquitin ligase recruitment ligand and a linker
•Bifunctional PROTAC molecules bind to the POI with one end, other end binds to
an E3 ligase to shorten the distance between them
•The E3 ligase then mediates the transfer of ubiquitin from an E2 enzyme to the POI,
and finally the ubiquitylated POI is knocked down by the proteasome
Proteolysis Targeting Chimera (PROTAC)
•Emerging drug discovery platform
•Promoting and recognizing the degradation of target proteins via the ubiquitin–
proteasome system (UPS)
•PROTACs are hetero-bifunctional molecules consisting of a ligand for the protein of
interest (POI), an E3 ubiquitin ligase recruitment ligand and a linker
•Bifunctional PROTAC molecules bind to the POI with one end, other end binds to
an E3 ligase to shorten the distance between them
•The E3 ligase then mediates the transfer of ubiquitin from an E2 enzyme to the POI,
and finally the ubiquitylated POI is knocked down by the proteasome
•PROTACs also have the advantages of low dosage and toxicity, as well as high
selectivity.
•PROTAC provides tremendous opportunity to apply targeted protein degradation
as a to accelerate the discovery of antiviral
In 2019, Yang and his team reported a PROTAC molecule that degrade the
hepatitis C virus (HCV) protease
Occupancy-driven pharmacology
(Event-based mechanism of action)
PROTACs only need to bind to
their target for as long as it takes
for the E3 ligase and POI to be
recruited together and the POI
degraded. In effect, they only have
to interact briefly to induce
proteolysis of the POI by the
proteasome.
selectivity.
•PROTAC provides tremendous opportunity to apply targeted protein degradation
as a to accelerate the discovery of antiviral
In 2019, Yang and his team reported a PROTAC molecule that degrade the
hepatitis C virus (HCV) protease
Occupancy-driven pharmacology
(Event-based mechanism of action)
PROTACs only need to bind to
their target for as long as it takes
for the E3 ligase and POI to be
recruited together and the POI
degraded. In effect, they only have
to interact briefly to induce
proteolysis of the POI by the
proteasome.
Ribonuclease Targeting Chimera (RIBOTAC)
•RIBOTAC is a new strategy for RNA degradation.
•RIBOTAC includes an RNA-binding small molecule and a ribonuclease (RNase) L-
recruiting module aiming to degrade the viral genome
•RIBOTACs locally recruit RNase L to the expected target to achieve the effect of
selective cleavage
•Targeted degradation strategy due to their ability to selectively degrade structured
RNA targets.
•RIBOTAC is a new strategy for RNA degradation.
•RIBOTAC includes an RNA-binding small molecule and a ribonuclease (RNase) L-
recruiting module aiming to degrade the viral genome
•RIBOTACs locally recruit RNase L to the expected target to achieve the effect of
selective cleavage
•Targeted degradation strategy due to their ability to selectively degrade structured
RNA targets.
Targeted Covalent Inhibitors (TCIs)
•Covalent inhibitors can interact with specific target proteins to form covalent
bonds that result in changes in the conformation of proteins, thus interfering
with the normal function of the protein
•The covalent binding with the target can be divided into two related but
discontinuous processes:
1.the inhibitor reversibly binds to the target, with weak electrophilic ligands
adjacent to the specific nucleophilic residues on the protein;
2.the ligand reacts with the functional groups involved in the protein to form
a covalent bond and this is irreversible
•Covalent inhibitors can interact with specific target proteins to form covalent
bonds that result in changes in the conformation of proteins, thus interfering
with the normal function of the protein
•The covalent binding with the target can be divided into two related but
discontinuous processes:
1.the inhibitor reversibly binds to the target, with weak electrophilic ligands
adjacent to the specific nucleophilic residues on the protein;
2.the ligand reacts with the functional groups involved in the protein to form
a covalent bond and this is irreversible
Topology-Matching Design
•Influenza A virus is an enveloped RNA virus, membrane anchors two viral
proteins that regulate interactions between the virion and host cells, i.e.
hemagglutinin (HA) and neuraminidase (NA)
•Nanoparticle-based inhibitor (nano-inhibitor) that has a matched
nanotopology to influenza virions and shows hetero-multivalent inhibitory
effects on hemagglutinin and neuraminidase
•The synthesized nano-inhibitor could neutralize the viral particle
extracellularly and block its attachment and enter host cells
Hetero-MNB:(Hetero-multivalent nanobowl)
•Influenza A virus is an enveloped RNA virus, membrane anchors two viral
proteins that regulate interactions between the virion and host cells, i.e.
hemagglutinin (HA) and neuraminidase (NA)
•Nanoparticle-based inhibitor (nano-inhibitor) that has a matched
nanotopology to influenza virions and shows hetero-multivalent inhibitory
effects on hemagglutinin and neuraminidase
•The synthesized nano-inhibitor could neutralize the viral particle
extracellularly and block its attachment and enter host cells
Hetero-MNB:(Hetero-multivalent nanobowl)
DNA microarray is an important tool that
has been efficiently utilized in the
development of host-protein target.
•DNA microarrays can be used to
measure the expression patterns of
thousands of genes in parallel,
generating clues to gene function that
can help to identify appropriate targets
for therapeutic intervention. They can
also be used to monitor changes in
gene expression in response to drug
treatments.
QSAR- Quantitative structure-activity
relationship (QSAR)
The fundamental principle of QSAR is that
biological properties are functions of molecular
structure.
•The QSAR is extensively used in the process
of drug invention process from hit to lead
optimization and identification.
•The statistical model is developed using
correlation studies and finally, the biological
activities of the new compounds is predicted
DNA Microarray QSAR
has been efficiently utilized in the
development of host-protein target.
•DNA microarrays can be used to
measure the expression patterns of
thousands of genes in parallel,
generating clues to gene function that
can help to identify appropriate targets
for therapeutic intervention. They can
also be used to monitor changes in
gene expression in response to drug
treatments.
QSAR- Quantitative structure-activity
relationship (QSAR)
The fundamental principle of QSAR is that
biological properties are functions of molecular
structure.
•The QSAR is extensively used in the process
of drug invention process from hit to lead
optimization and identification.
•The statistical model is developed using
correlation studies and finally, the biological
activities of the new compounds is predicted
DNA Microarray QSAR
Antiviral Drug Delivery System
•Human serum albumin (HSA) is the most abundant protein in sera (30–50
g/L in human serum)
•As an inherent protein in blood, it does not exhibit immunogenicity.
•Non-covalent binding of small molecular drugs to HAS protects them from
enzymatic degradation and renal clearance, providing slower clearance and
extended half-life
•HSA is an ideal drug carrier for targeting delivery and improving the
pharmacokinetic profile (half-life extension) of drugs.
•Cholesterol is abundant in eukaryotic cell membranes.
•Cholesterol conjugation can spontaneously insert modified nucleic acids and
peptides into lipid bilayers and their subsequent uptake by cells
•Human serum albumin (HSA) is the most abundant protein in sera (30–50
g/L in human serum)
•As an inherent protein in blood, it does not exhibit immunogenicity.
•Non-covalent binding of small molecular drugs to HAS protects them from
enzymatic degradation and renal clearance, providing slower clearance and
extended half-life
•HSA is an ideal drug carrier for targeting delivery and improving the
pharmacokinetic profile (half-life extension) of drugs.
•Cholesterol is abundant in eukaryotic cell membranes.
•Cholesterol conjugation can spontaneously insert modified nucleic acids and
peptides into lipid bilayers and their subsequent uptake by cells
Drug Resistance in Antiviral Therapy
❑ Mutation rate of the virus
➢ Higher the mutation rate, the more rapidly resistance can
develop
Factors Affecting the Development of Drug Resistance
Viral mutation rates
Fidelity of the polymerases
➢ Higher the mutation rate, the more rapidly resistance can
develop
Factors Affecting the Development of Drug Resistance
Viral mutation rates
Fidelity of the polymerases
RNA viruses DNA viruses
Low fidelity RNA polymerases
Highest mutation rates
one mutation per genome per
replication cycle
DNA polymerases include
proofreading 3’- 5’ exonuclease
lower mutation rates
High fidelity DNA polymerases
DNA virus mutation rate: Approx. 10
-8
per incorporated nucleotide, i.e, per
nucleotide per replication cycle).
RNA virus mutation rate:10
-4
to 10
-6
substitutions per nucleotide per round of
copying
•Rate of nucleotide substitution in viral genome is approx. 100-10,000 fold
higher than the average rate in eukaryotic DNA.
Low fidelity RNA polymerases
Highest mutation rates
one mutation per genome per
replication cycle
DNA polymerases include
proofreading 3’- 5’ exonuclease
lower mutation rates
High fidelity DNA polymerases
DNA virus mutation rate: Approx. 10
-8
per incorporated nucleotide, i.e, per
nucleotide per replication cycle).
RNA virus mutation rate:10
-4
to 10
-6
substitutions per nucleotide per round of
copying
•Rate of nucleotide substitution in viral genome is approx. 100-10,000 fold
higher than the average rate in eukaryotic DNA.
❑ Target size for mutation
➢ The more sites where mutations can confer drug resistance,
the more rapidly resistance can arise
ACV
any mutation that substantially reduces viral TK
activity results in resistance
Homopolymeric runs in the HSV tk gene (e.g., a run of 7
Guanosine GGGGGGG ) are hot spots for frame-shift
mutations that confer ACV resistance
➢ The more sites where mutations can confer drug resistance,
the more rapidly resistance can arise
ACV
any mutation that substantially reduces viral TK
activity results in resistance
Homopolymeric runs in the HSV tk gene (e.g., a run of 7
Guanosine GGGGGGG ) are hot spots for frame-shift
mutations that confer ACV resistance
❑ Replication rate
➢The more copies of viral genomes produced, the more
opportunities for resistance to arise
❑ Pre-existing size of the population
Immunocompetent
contain much less virus
HSV or VZV HIV
Immuno-compromised
replication and mutation
at a much lower rate
contain more virus
replication and mutation at
a much higher rate
ResistanceNo Resistance
➢The more copies of viral genomes produced, the more
opportunities for resistance to arise
❑ Pre-existing size of the population
Immunocompetent
contain much less virus
HSV or VZV HIV
Immuno-compromised
replication and mutation
at a much lower rate
contain more virus
replication and mutation at
a much higher rate
ResistanceNo Resistance
❑ Fitness
‘How well a genetic variant reproduces relative to other genetic
variants, which can include wild-type’
The more fit, the more likely resistance will occur
For a virus to cause disease that is resistant to an antiviral drug,
it must mutate not only to evade drug action, but also to retain
pathogenicity.
‘How well a genetic variant reproduces relative to other genetic
variants, which can include wild-type’
The more fit, the more likely resistance will occur
For a virus to cause disease that is resistant to an antiviral drug,
it must mutate not only to evade drug action, but also to retain
pathogenicity.
emergence of drug resistance
These various factors
mathematical modelling
How different viral infections are treated
HIV infections are now treated with combinations of antiviral
drugs, whereas HSV infections are treated with single agents
These various factors
mathematical modelling
How different viral infections are treated
HIV infections are now treated with combinations of antiviral
drugs, whereas HSV infections are treated with single agents
Clinical Impact of Drug Resistance
Evidence of treatment failure
to isolate drug-resistant virus
Treatment with second drug to which the virus is
susceptible
Persistent infections
Acute Infections → immune sysytem
Accumulation of resistance mutations
↓ Drug sucseptibility
↓ Efficacy of drug
Evidence of treatment failure
to isolate drug-resistant virus
Treatment with second drug to which the virus is
susceptible
Persistent infections
Acute Infections → immune sysytem
Accumulation of resistance mutations
↓ Drug sucseptibility
↓ Efficacy of drug
❑ Continued replication in the presence of drug selects for even greater
levels of resistance to each administered drug and progressive cross-
resistance to drugs of the same class
❑ Drug-resistant viruses can be transmitted to other individuals
❑ In the case of HIV, resistant virus in blood or genital secretions can be
transmitted during sex, needle sharing, or childbirth
levels of resistance to each administered drug and progressive cross-
resistance to drugs of the same class
❑ Drug-resistant viruses can be transmitted to other individuals
❑ In the case of HIV, resistant virus in blood or genital secretions can be
transmitted during sex, needle sharing, or childbirth
Strategies to Combat Drug Resistance
➢ Test viruses for drug resistance before choosing antiviral
regimens
Ineffective Drug
↓ diminishing cost, toxicity, and inconvenience
Effective DrugOr
HIV, HCV &
HBV
Genotypic Assay Phenotypic Assay
Detecting mutations at the
level of DNA or RNA
Measuring changes in drug
susceptibility
➢ Test viruses for drug resistance before choosing antiviral
regimens
Ineffective Drug
↓ diminishing cost, toxicity, and inconvenience
Effective DrugOr
HIV, HCV &
HBV
Genotypic Assay Phenotypic Assay
Detecting mutations at the
level of DNA or RNA
Measuring changes in drug
susceptibility
➢ Combination chemotherapy
1.The probability of a virus being resistant to multiple different drugs is
the product of the probabilities of resistance to each drug
2. The combination is likely to suppress replication more completely
than would any of the drugs alone.
3.Members of the combination might synergize, providing even
greater efficacy
4. Synergy might allow lower doses of each drug, reducing toxicity
5. A mutation conferring resistance to one drug in a combination
might yield clinical advantages, for example, by making the virus
less fit or by sensitizing otherwise resistant viruses to a second
drug
1.The probability of a virus being resistant to multiple different drugs is
the product of the probabilities of resistance to each drug
2. The combination is likely to suppress replication more completely
than would any of the drugs alone.
3.Members of the combination might synergize, providing even
greater efficacy
4. Synergy might allow lower doses of each drug, reducing toxicity
5. A mutation conferring resistance to one drug in a combination
might yield clinical advantages, for example, by making the virus
less fit or by sensitizing otherwise resistant viruses to a second
drug
Why not always use combination chemotherapy?
➢Adding additional drugs adds additional toxicities and pharmacologic problems,
which sometimes exacerbate those of the first drug
➢Combination regimens can be difficult for the patient, reducing compliance with
the prescription
Sometimes too few drugs are available to combine or if there are multiple
drugs, they entail similar mechanisms of action and resistance
Inflexible fixed dose ratio, incompatible pharmacokinetics, increased
toxicity, and physician and pharmacist ignorance of content
➢Adding additional drugs adds additional toxicities and pharmacologic problems,
which sometimes exacerbate those of the first drug
➢Combination regimens can be difficult for the patient, reducing compliance with
the prescription
Sometimes too few drugs are available to combine or if there are multiple
drugs, they entail similar mechanisms of action and resistance
Inflexible fixed dose ratio, incompatible pharmacokinetics, increased
toxicity, and physician and pharmacist ignorance of content
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