2. Objectives
Describe the different types of antiviral drugs
Explain the chemical structure-activity
relationships of the drugs
Chemical modification for specific actions
The physical and chemical properties and
stability of the drugs
2
4. 1.0 Introduction: Properties of Viruses
Viruses are cellular parasites composed of a
nucleic acid core surrounded by a proteinaceous
outer shell.
They utilize the biochemical apparatus of the cell
to synthesize the virus-specific proteins required
for production of the mature viral particle.
Matured viruses possess only one type of nucleic
acid (either DNA or RNA).
4
6. 1.0 Introduction: Viral Classification
It is based on various characteristics such as
1. Nucleic acid content (DNA or RNA viruses)
2. Morphology
3. Site of replication in the cell
4. Shell composition (nonenveloped, enveloped)
6
7. Replication cycle
There are six basic stages in the life cycle of viruses:
1. Attachment
Specific binding between viral capsid proteins (protein shell
of a virus) and specific receptors on the host cellular surface.
2. Penetration
Viruses enter the host cell through receptor mediated
endocytosis or membrane fusion (viral entry).
Introduction: Replicative Cycle of Virus
7
8. 3. Uncoating
The viral capsid is degraded by viral enzymes or host
enzymes
4. Replication
(i) Synthesis of viral messenger RNA (mRNA)
(ii) Viral protein synthesis
(iii) Assembly of viral proteins
(iv) Viral genome replication.
Introduction: Replicative Cycle of Virus
8
9. 5. Post-translational modification of the viral proteins,
follows the assembly of the virus particles (Maturation).
In HIV virus, the maturation occurs after the virus has
been released from the host cell.
6. Viruses are released from the host cell by
Lysis- this process kills the cell by bursting its membrane.
Budding - viruses (e.g., HIV) are released from the host cell
by budding.
In budding virus acquires its envelope from modified piece
of the host's plasma membrane.
Introduction: Replicative Cycle of Virus
9
11. 1.0 Introduction: Preventable Stages of
Virus Infection
Virus infection can be prevented in three stages
prior to virus replication:
Attachment of the virion to the host cell
Its entry into the cell
Release of viral nucleic acid from protein coat.
11
17. 2.0 Antiviral Chemotherapy
NH2.HCl
Properties
Soluble in water and insoluble in alcohol.
Use in prevention and treatment of influenza
caused by influenza A virus.
Distributed to all body fluids and tissues and
excreted largely unchanged in the urine.
The mechanism of Amantadine's antiviral
activity involves interference with a viral
protein, M2 (an ion channel),which is
required for the viral particle to become
"uncoated" once taken inside a cell by
endocytosis.
2.1 Amantadine
1-Adamantanamine Hydrochloride (Symadine)
17
18. 2.0 Antiviral Chemotherapy
A branched homologue of amantadine
with similar antiviral properties.
Is effective for the prophylaxis and
early treatment of infection caused
by influenza A viral subtypes.
Mechanism of action is same as
amantadine
CH
H3C NH2.HCl
2.2 Rimantadine hydrochloride
-methyl-1-adamantane methylamine hydrochloride
18
24. 3.1 DNA Polymerase Inhibitors-Idoxuridine
Idoxuridine [ 2’-deoxy-5-iodouridine (IUdR)]
Thymidine analogue (Iodinated pyrimidine)
Active only against DNA viruses
Treatment of herpes simplex
• Idoxuridine triphosphate acts
as both inhibitor and a substrate
of viral DNA polymerase.
O
HO
HO
N
HN
O
O
I
1'
2'
3'
4'
5' 1
2
3 4
5
6
24
25. 3.1 DNA Polymerase Inhibitors-
Bioctivation of thymidne
O
HO
HO
N
HN
O
O
CH3
O
P-O
HO
N
HN
O
O
CH3
O
P-P-O
HO
N
HN
O
O
CH3
O
P-P-P-O
HO
N
HN
O
O
CH3
Thymidine
monophosphate
Thymidine
diphosphate
Thymidine
triphosphate
Thymidine
thymidylate
kinase
kinase
kinase
P=
P
O
HO
OH
Thymidine triphosphate is required for the DNA synthesis. 25
26. 3.1 DNA Polymerase Inhibitors-
Idoxuridine – Mode of action
Thymidine triphosphate is required for the
DNA synthesis.
Idoxuridylic acid substitutes for
deoxythymidylic acid in the synthesis of
DNA owing to the similar van der Waals’
radii of iodine and the methyl group.
26
27. 3.1 DNA polymerase inhibitors-
Idoxuridine – Mechanism of action
O
HO
HO
N
HN
O
O
I
O
P-O
HO
N
HN
O
O
I
O
P-P-O
HO
N
HN
O
O
I
O
P-P-P-O
HO
N
HN
O
O
I
Idoxuridine
monophosphate
Idoxuridine
diphosphate
Idoxuridine
triphosphate
Idoxuridine
thymidylate
kinase
kinase
kinase
P=
P
O
HO
OH
Idoxuridine triphosphate is incorporated in both cellular
and viral DNA chain Synthesis of DNA is inhibited in both.
27
28. 3.1 DNA Polymerase Inhibitors-
Idoxuridine – Mode of Action & Selectivity
Idoxuridine is phosphorylated by viral thymidylate
kinase to the monophosphate which is bioactivated
further to the triphosphate.
Idoxuridine triphosphate acts as both inhibitor and a
substrate of viral DNA polymerase.
Idoxuridine triphosphate is incorporated in both
cellular and viral DNA chain.
Therefore, the synthesis of DNA is inhibited in both
viral and cellular DNA due to the poor selectivity.
28
29. 3.2 DNA Polymerase Inhibitors-
Acycloguanosines
N
N
HN
N
O
H2N
O
HO
Acyclovir (ACV) (Zovirax)
9-[(2-hydroxyethoxy)methyl] Guanine
2’-Deoxyguanosine
O
HO
HO
1'
2'
3'
4'
5'
N
N
HN
N
O
H2N
Acyclovir
29
30. 3.2 Acyclovir
Acyclovir triphosphate has an affinity 100 times
greater for viral DNA polymerase than for human
DNA polymerase.
Has potent activity against several DNA viruses,
HSV-1 and HSV-2, varicella-zoster virus (VZV),
and Epstein-Barr virus.
It is the drug of choice for the treatment of genital
herpes.
30
31. Chemically stable, white, crystalline solid, slightly
soluble in water.
It has amphoteric properties (pKa values 2.27 and
9.25), thus increases the solubility by both strong
acids and strong bases.
The injectable form is the sodium salt which is
supplied as a lyophilized powder, equivalent to 50
mg of active ingredient dissolved in 10 mL of
sterile water for injection.
4.3.1 Acyclovir- properties
31
32. 3.2 Acyclovir: Mode of Action
Mechanism of inhibition involves the chain
termination resulted from the lack of formation of
the 3’,5’-phosphodiester bond.
The acyclic nucleoside is transported into infected
cells.
Then it is phosphorylated selectively by viral
thymidylate kinase to the monophosphate,
Further phosphorylation by cellular enzymes forms
the triphosphate.
32
33. 3.2 Acyclovir- Mode of action
N
N
HN
N
O
H2N
O
HO
N
N
HN
N
O
H2N
O
P-O
N
N
HN
N
O
H2N
O
P-P-O
N
N
HN
N
O
H2N
O
P-P-P-O
O
HO
O
1'
2'
3'
4'
5'
N
N
HN
N
O
H2N
P O
O
HO
O
Thymine
O
P
O
HO
O
O
Guanine
viral
Thymidylate
kinase
Cellular
kinase
Cellular
kinase
Chain termination
Due to the lack of
3’-OH on acyclovir
P = phosphate
33
34. 3.3 Ganciclovir
An analogue of acyclovir,
having an additional
hydroxymethyl group on
the acyclic side chain.
Maintains the activity
against HSV and VZV
N
N
HN
N
O
H2N
O
HO
HO
9-[(1,3-dihydroxy-2-propoxy)
Methyl}-guanine, DHPG
Cytovene 34
35. 3.3. Ganciclovir – Mode of action
The mode of action is similar to Acyclovir.
Gancyclovir is phosphorylated intracellularly by a virally
encoded protein kinase to the monophosphate.
Then the monophosphate is catalyzed to the triphosphate
by host enzymes in the infected cell.
Selectivity towards the infected cell is achieved in greater
than 10-fold than in uninfected cells.
Ganciclovir triphosphate is a selective inhibitor of
viral DNA polymerase, which is incorporated into
viral DNA to cause chain termination.
35
37. 3.4 RNA polymerase inhibitor- Ribavirin
Used for treatment of severe
lower respiratory infections
caused by RSV(Human respiratory
syncytial virus).
Ribavirin occurs as
a white, crystalline,
polymorphic solid
soluble in water and
chemically stable.
1-D-ribofuranosyl-1H-1,2,4-
triazole-3-carboxamide
Virazole
O
HO
HO
N
OH
N
HN
O
H2N
1
2
3
4
37
38. The nucleoside is bioactivated to monophosphate (RMP)
and triphosphate (RTP) by viral and cellular kinases and
cellular phosphorylating enzymes
RMP inhibits inosine monophosphate (IMP) dehydrogenase
hence prevents the conversion of IMP to xanthine
monophosphate (XMP).
XMP is required for guanosine triphosphate (GTP) synthesis.
RTP inhibits viral RNA polymerases
3.4 Ribavirin- Mode of Action
38
39. IMP XMP
IMP
dehydrogenase
Viral RNA
polymerase
RNA
RMP
RTP
RDP
3.4 Ribavirin- Mode of Action
O
HO
O
1'
2'
3'
4'
5'
N
N
HN
N
O
H2N
P O
O
HO
O
Thymine
O
P
O
HO
O
O
1,2,4-triazole
HO
O
P-O
HO
N
N
HN
N
O
H2N
OH
O
P-O
HO
N
N
HN
N
H
O
O
OH
OH
OH
OH
O
HO
HO
N
OH
N
HN
O
H2N O
P-O
HO
N
OH
N
HN
O
H2N
O
P-P-O
HO
N
OH
N
HN
O
H2N
O
P-P-P-O
HO
N
OH
N
HN
O
H2N
39
41. Reverse Transcribing Viruses
Retrovirus: An RNA virus (a virus composed not of
DNA but of RNA).
Retroviruses have an enzyme called reverse
transcriptase that gives them the unique property of
transcribing RNA (their RNA) into DNA.
The retroviral DNA can then integrate into the
chromosomal DNA of the host cell
- The virus thereafter replicates as part of host cell’s DNA
41
42. 4.1 Nucleoside Reverse Transcriptase
Inhibitors - Zidovudine
O
HO
N3
N
HN
O
O
CH3
1'
2'
3'
4'
5' 1
2
3 4
5
6
Thymidine analog
Active against retroviruses
Zidovudine,
Azidothymidine (AZT)
3’-azido-3’,2’-deoxythymidine
42
43. 4.1. Zidovudine (Azidothymidine )- Mode of
Action
The AZT is converted to the monophosphate by retroviral
thymidylate kinase and eventually to the triphosphate.
AZT triphosphate (AZTTP) is utilized by reverse
transcriptase for incorporation into an incomplete proviral
DNA.
The DNA chain terminates at the site of AZT
incorporation because 3’,5’-phosphodiester bond cannot
form with another nucleoside triphosphate.
That is the inhibition of reverse transcriptase.
43
44. 4.1. Zidovudine- Mode of Action
O
HO
N3
N
HN
O
O
CH3
O
P-O
N3
N
HN
O
O
CH3
O
P-P-O
N3
N
HN
O
O
CH3
O
P-P-P-O
N3
N
HN
O
O
CH3
AZTMP
AZTDP
AZTTP
AZT
kinase
kinase
P =
P
O
HO
OH
O
HO
O
1'
2'
3'
4'
5'
N
N
HN
N
O
H2N
P O
O
HO
O
Thymine
O
P
O
HO
O
O
Thymine
N3
Reverse
transcriptase
Proviral
DNA synthesis
The DNA chain terminates at the site of AZT incorporation
because 3’,5’-phosphodiester bond cannot form with another
nucleoside triphosphate. 44
45. 4.2. Nucleoside Reverse Transcriptase
Inhibitors
O
HO
N
HN
O
O
CH3
1'
2'
3'
4'
5' 1
2
3 4
5
6
O
HO
N
N
NH2
O
HO
S
O
HO
N
N
NH2
O
N
N
HN
N
O
O
HO
Other derivatives of AZT includes:-
Stavudine
d4T
Zalcitabine (ddC)
Lamivudine
3TC
Didanosine
(ddI)
45
46. 4.2. 5-Bromovinyl-2’-deoxyuridine (BVDU)
Effective against herpes
zoster
Stimulate tumor growth
in animal model
Activated by viral
thymidine kinase
enzyme that causes
phosphorylation.
O
HO
HO
N
HN
O
O
Br
46
47. 4.2b. Fluoroiodoaracytosine (FIAC)
An anlog of cytarabine
A pyrimidine nucleoside as
potent as BVDU.
Preferentially phosphorylated
by HSV-specified thymidine
kinase.
Very effective on herpes
viruses
Selective inhibition against
viral enzyme (1000x greater
than human enzyme) 47
N
O
N
NH2
I
OH
HO
O
HO
F
1-beta-D-arabinofuranosyl-2'-fluoro-5-iodocytosine
51. 4.3 Non-nucleosides reverse
transcriptase inhibitors (NNRTIs)
They do not require bioactivation.
They bind to an allosteric site distinct form the
substrate (nucleoside triphosphate)-binding site of
reverse transcriptase to cause a noncompetitive
inhibition of the enzyme.
They inhibit HIV-1 at nanomolar concentrations.
They have a high selectivity against HIV-1 RT.
51
52. 4.3 Non-nucleosides reverse
transcriptase inhibitors (NNRTIs)
They have high therapeutic indexes and do not inhibit
mammalian DNA polymerases.
They have an additive or synergistic action against HIV.
They are used in combination with nucleoside reverse
transcriptase inhibitors for the treatment of HIV.
Utilization in combinations with the nucleosides reduce the
incidence of toxicity of nucleosides analogs and discourage
the emergence of viral resistance.
52
53. 4.4 Interferon
Interferons are a family of naturally-occurring proteins
produced by cells of the immune system
Interferons provide normal mechanism of resistance
against viral infection.
Interferons direct the immune system's attack on
viruses, bacteria, tumors and other foreign substances
that invade the body, by slowing, blocking, or
changing its growth or function.
-
53
54. 4.4 Interferon
Consisting of a mixture of small
proteins with molecular weights
ranging from 20,000 to 160,000.
Human interferons have been
classified into three major types.
Interferon type I: Type I IFNs bind to
a specific cell surface receptor
complex known as the IFN-α receptor
(IFNAR) that consists of IFNAR1
and IFNAR2 chains. The type I
interferons present in humans are
IFN-α, IFN-β and IFN-ω.
Interferon type II: Binds to IFNGR
that consists of IFNGR1 and
IFNGR2 chains. In humans this is
IFN-γ.
54
human interferon-alpha
55. As an infected cell dies from a cytolytic virus, viral
particles are released that can infect nearby cells.
The infected warns neighboring cells of a viral presence
by releasing interferon.
The neighboring cells, in response to interferon, produce
large amounts of an enzyme known as protein kinase R
(PKR).
This enzyme phosphorylates a protein known as eIF-2 in
response to new viral infections
4.4 Interferon: Mechanism of Action
55
56. 4.4 Interferon: Mechanism of Action
The phosphorylated eIF-2 forms an inactive complex with another
protein, called eIF2B, to reduce protein synthesis within the cell.
Another cellular enzyme, RNAse L also induced following PKR
activation destroys RNA within the cells to further reduce protein
synthesis of both viral and host genes.
Inhibited protein synthesis destroys both the virus and infected host
cells.
In addition, interferons induce production of hundreds of other
proteins known collectively as interferon-stimulated genes (ISGs) that
have roles in combating viruses.
56
