Antiviral Chemotherapy
المؤلف:
Stefan Riedel, Jeffery A. Hobden, Steve Miller, Stephen A. Morse, Timothy A. Mietzner, Barbara Detrick, Thomas G. Mitchell, Judy A. Sakanari, Peter Hotez, Rojelio Mejia
المصدر:
Jawetz, Melnick, & Adelberg’s Medical Microbiology
الجزء والصفحة:
28e , p449-451
2025-10-28
50
Unlike viruses, bacteria and protozoans do not rely on host cellular machinery for replication, so processes specific to these organisms provide ideal targets for the development of antibacterial and antiprotozoal drugs. Because viruses are obligate intracellular parasites, antiviral agents must be capable of selectively inhibiting viral functions without damaging the host, making the development of such drugs very difficult. Another limitation is that many rounds of virus replication occur during the incubation period and the virus has spread before symptoms appear, making drug treatment after the development of clinical symptoms relatively ineffective.
There is a need for antiviral drugs active against viruses for which vaccines are not available or not highly effective because of a multiplicity of serotypes (eg, rhinoviruses) or because of constantly changing viral antigens (eg, influenza, HIV). Antivirals can be used to treat established infections when vaccines would not be effective. Antivirals are needed to reduce morbidity and economic loss caused by viral infections and to treat increasing numbers of immunosuppressed patients who are at increased risk of severe disease.
Molecular virology studies are succeeding in identifying virus-specific functions that can serve as targets for antiviral therapy. Stages during viral infections that could be targeted include attachment of virus to host cells, uncoating of the viral genome, viral nucleic acid synthesis, translation of viral proteins, and assembly and release of progeny virus particles. It has been very difficult to develop antivirals that can distinguish viral from host replicative processes, but there have been successful drugs developed, particularly for chronic infections (eg, HIV, hepatitis C). A number of compounds have been developed that are of value in treatment of viral diseases (Table 1). The mechanisms of action vary among antivirals, and can target a viral protein enzymatic activity or block host–virus protein interaction. Some drugs must be activated by enzymes in the cell before it can act as an inhibitor of viral replication; the most selective drugs are activated by a virus encoded enzyme in the infected cell.
Table1. Examples of Antiviral Compounds Used for Treatment of Viral Infections
Future work is necessary to minimize the emergence of drug-resistant variant viruses, to reduce drug toxicities, to design more specific antivirals based on molecular insights into the structure of other viral targets, and to develop antivirals for viruses for which no drugs currently exist.
A. Nucleoside and Nucleotide Analogs
The majority of available antiviral agents are nucleoside analogs. They inhibit nucleic acid replication by inhibition of viral polymerases essential for nucleic acid replication. In addition, some analogs are incorporated into the nucleic acid as chain terminators and block further synthesis.
Analogs can inhibit cellular enzymes as well as virus encoded enzymes. The most effective analogs are those that are able to specifically inhibit virus-encoded enzymes, with minimal inhibition of analogous host cell enzymes. Because of high mutation rates, virus variants resistant to the drug usually arise over time, sometimes quite rapidly. The use of combinations of antiviral drugs can delay the emergence of resistant variants (eg, “triple-drug” therapy used to treat HIV infections).
B. Reverse Transcriptase Inhibitors
Nonnucleoside reverse transcriptase inhibitors act by binding directly to virally encoded reverse transcriptase and inhibiting its activity. However, resistant mutants emerge rapidly, making these useful only in the context of multi drug therapy.
C. Protease Inhibitors
Protease inhibitors were first designed by computer modeling as peptidomimetic agents that fit into the active site of the HIV protease enzyme. Such drugs inhibit the viral pro tease that is required at the late stage of the replicative cycle to cleave the viral gag and gag-pol polypeptide precursors to form the mature virion core and activate the reverse transcriptase that will be used in the next round of infection. Pro tease inhibitors have been used successfully for treatment of HIV and HCV infections.
D. Integrase Inhibitors
HIV integrase inhibitors block the activity of viral integrase, a key enzyme in HIV replication. Without integration of virally encoded DNA into the host chromosome, the life cycle cannot continue. Raltegravir was the first integrase inhibitor to be approved in 2007.
E. Fusion Inhibitors
HIV fusion inhibitors act by disrupting the fusion of viral envelope with the cell membrane, preventing cellular infection. The prototype agent, enfuvirtide, is a peptide that binds to gp41 and blocks the required conformational change that initiates membrane fusion.
F. Other Types of Antiviral Agents
A number of other types of compounds have been shown to possess some antiviral activity under certain conditions.
Amantadine and rimantadine specifically inhibit influenza A viruses by blocking viral uncoating. They must be administered very early in infection to have a significant effect.
Oseltamivir is a neuraminidase inhibitor that prevents the release of influenza virus particles from infected cells.
Foscarnet (phosphonoformic acid) is an organic analog of inorganic pyrophosphate. It selectively inhibits viral DNA polymerases and reverse transcriptases at the pyrophosphate binding site.
Acyclovir is a guanosine analog DNA polymerase inhibitor used for the treatment of HSV and varicella-zoster virus infections. The prodrug valacyclovir is an esterified version that can be taken orally and is metabolized to acyclovir.
Ganciclovir is a nucleoside DNA polymerase inhibitor active against CMV whose specificity comes from phosphorylation by virus-specific kinases only in virally infected cells. Valganciclovir is the orally available prodrug for ganciclovir.
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