Antiviral Chemotherapy

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.





Drug Nucleoside Analog Mechanism of Action Viral Spectrum
 
Acyclovir Yes Viral polymerase inhibitor Herpes simplex, varicella-zoster
Amantadine No Blocks viral uncoating Influenza A
Cidofovir No Viral polymerase inhibitor Cytomegalovirus, herpes simplex, polyomavirus
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
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 inhibitor Herpes simplex, 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 2. Properties of Human Interferons.



Property Type
Alpha Beta Gamma
IFN-? IFN-? IFN-?
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 cost-effective method of prevention of serious viral infections.
Mucosal immunity (local IgA) is important in resistance to infection by viruses that replicate exclusively in mucosal membranes (rhinoviruses, influenza viruses, rotaviruses). Viruses that have a viremic mode of spread (polio, hepatitis, measles) are controlled by serum antibodies. Cell-mediated immunity also is involved in protection against systemic infections (measles, herpes).


Table 3 Comparison of Characteristics of Killed and Live Viral Vaccines


Characteristic Killed Vaccine Live Vaccine
Number of doses Multiple Single
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
Stability at room temperature High Low