Antiviral Chemotherapy
There is a need for antiviral drugs active against viruses for which
vaccines are not available or not highly effective. Antivirals are needed to
reduce morbidity and economic loss due to viral infections and to treat
increasing numbers of immunosuppressed patients who are at increased
risk of infection.
Types of antiviral drugs:
* Nucleoside Analogs
The majority of available antiviral agents are nucleoside analogs. They
inhibit nucleic acid replication by inhibition of polymerases for nucleic
acid replication. In addition, some analogs can be incorporated into the
nucleic acid and block further synthesis or alter its function.
* Nucleotide Analogs
Nucleotide analogs differ from nucleoside analogs in having an
attached phosphate group. Their ability to persist in cells for long periods
of time increases their potency. Cidofovir is an example.
* Nonnucleoside Reverse Transcriptase Inhibitors
Nevirapine was the first member of the class of nonnucleoside reverse
transcriptase inhibitors. It does not require phosphorylation for activity
and does not compete with nucleoside triphosphates. It acts by binding
directly to reverse transcriptase and disrupting the enzyme's catalytic site.
* Protease Inhibitors
Saquinavir was the first protease inhibitor to be approved for
treatment of HIV infection. Such drugs inhibit the viral protease that is
required at the late stage of the replicative cycle to cleave the viral
polypeptide precursors to form the mature virion core and activate the
reverse transcriptase that will be used in the next round of infection.
Protease inhibitors include indinavir and ritonavir .
* Fusion Inhibitor
Fuzeon is a large peptide that blocks the virus and cellular membrane
fusion step involved in entry of HIV-1 into cells.
Other Types of Antiviral Agents
* Amantadine and Rimantadine
These synthetic amines specifically inhibit influenza A viruses by
blocking viral uncoating.
* Foscarnet (Phosphonoformic Acid, PFA)
Foscarnet, an organic analog of inorganic pyrophosphate, selectively
inhibits viral DNA polymerases and reverse transcriptases at the
pyrophosphate-binding site.
* Methisazone
Methisazone is of historical interest as an inhibitor of poxviruses. It
blocked a late stage in viral replication, resulting in the formation of
immature, noninfectious virus particles.
Table 3: Examples of Antiviral Compounds Used for Treatment of
Viral Infections.
Drug
Acyclovir
Nucleoside Mechanism of
Viral Spectrum
Analog
Action
Yes
Viral polymerase Herpes simplex, varicellainhibitor
zoster
Amantadine
No
Blocks viral
uncoating
Influenza A
Cidofovir
No
Didanosine
(ddI)
Yes
Reverse
transcriptase
inhibitor
HIV-1, HIV-2
Foscarnet
No
Viral polymerase
inhibitor
Herpesviruses, HIV-1,
HBV
Fuzeon
No
HIV fusion
inhibitor (blocks
viral entry)
HIV-1
Ganciclovir
Yes
Viral polymerase
inhibitor
Cytomegalovirus
Indinavir
No
HIV protease
inhibitor
HIV-1, HIV-2
Viral polymerase Cytomegalovirus, herpes
inhibitor
simplex, polyomavirus
Lamivudine
(3TC)
Yes
Reverse
transcriptase
inhibitor
HIV-1, HIV-2, HBV
Nevirapine
No
Reverse
transcriptase
inhibitor
HIV-1
Ribavirin
Yes
Perhaps blocks
capping of viral
mRNA
Respiratory syncytial
virus, influenza A and B,
Lassa fever, hepatitis C,
others
Ritonavir
No
HIV protease
inhibitor
HIV-1, HIV-2
Saquinavir
No
HIV protease
inhibitor
HIV-1, HIV-2
Stavudine
(d4T)
Yes
Reverse
transcriptase
inhibitor
HIV-1, HIV-2
Trifluridine
Yes
Viral polymerase
Herpes simplex,
inhibitor
cytomegalovirus, vaccinia
Valacyclovir
Yes
Viral polymerase
inhibitor
Herpesviruses
Vidarabine
Yes
Viral polymerase
inhibitor
Herpesviruses, vaccinia,
HBV
Zalcitabine
(ddC)
Yes
Reverse
transcriptase
inhibitor
HIV-1, HIV-2, HBV
Zidovudine
(AZT)
Yes
Reverse
transcriptase
inhibitor
HIV-1, HIV-2, HTLV-1
Interferons
Interferons (IFNs) are host-coded proteins that are members of the
large cytokine family and which inhibit viral replication. They are
produced very quickly (within hours) in response to viral infection or
other inducers and are one of the body's first responders in the defense
against viral infection. Interferons are central to the innate antiviral
immune response. They also modulate humoral and cellular immunity
and have broad cell growth regulatory activities.
Properties of Interferons
There are multiple species of interferons that fall into three general
groups as follow:
Table 4: Properties of Human Interferons.
Type
Property
Current nomenclature
Alpha
IFN-α
Beta
IFN-β
Gamma
IFN-γ
Former designation
Leukocyte
Fibroblast
Immune
interferon
Type designation
Type I
Type I
Type II
Number of genes that
code for family
20
1
1
Principal cell source
Most cell types Most cell types
Lymphocytes
Inducing agent
Viruses; dsRNA Viruses; dsRNA
Mitogens
Stability at pH 2.0
Stable
Stable
Labile
Introns in genes
No
No
Yes
Chromosomal location
of genes
9
9
12
Size of secreted protein
(number of amino
acids)
165
166
143
Chromosomal location
of IFN receptor genes
21
21
6
Viral Vaccines
The purpose of viral vaccines is to utilize the immune response of the
host to prevent viral disease. Several vaccines have proved to be effective
at reducing the incidence of viral disease Vaccination is the most costeffective method of prevention of serious viral infections.
Table 5: Comparison of Characteristics of Killed and Live Viral
Vaccines
Characteristic
Live Vaccine
Number of doses
Killed
Vaccine
Multiple
Need for adjuvant
Yes
No
Duration of immunity
Shorter
Longer
Effectiveness of protection (more closely
mimics natural infection)
Lower
Greater
Immunoglobulins produced
IgG
IgA and IgG
Mucosal immunity produced
Poor
Yes
Cell-mediated immunity produced
Poor
Yes
Residual virulent virus in vaccine
Possible
No
Reversion to virulence
No
Possible
Excretion of vaccine virus and transmission to
nonimmune contacts
No
Possible
Interference by other viruses in host
No
Possible
High
Low
Stability at room temperature
Single