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.


Table 1. Examples of Antiviral Compounds Used for Treatment of Viral Infections.


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