Antiviral agents selective toxicity

Idoxuridine (9.7) and trifluridine (9.8) are antiviral agents that are phosphorylated to their active form in virus-infected cells, and thus show specificity for two reasons their higher affinity for the viral enzyme, and the higher phosphorylase levels in viral-infected than in normal cells. Both compounds have been used locally on lesions of HSV-1 and HSV-2 (the latter of which causes genital herpes, now reaching epidemic proportions) with fair success. They are rather toxic if administered parenterally, as are all moderately selective antimetabolities. 

Which one of the following antiviral agents exhibits the greatest selective toxicity for the invading virus ... 

Viruses present a more difficult problem of chemotherapy than do higher organisms, e.g. bacteria, for they are intracellular parasites that use the metabolism of host cells. Highly selective toxicity is, therefore, harder to achieve. Identification of differences between viral and human metabolism has led to the development of effective antiviral agents, whose roles are increasingly well defined. 

Several compounds are known that are inhibitory to mammalian viruses in tissue culture, but only a few can be used in the treatment of human viral infections. The main problem in designing and developing antiviral agents is the lack of selective toxicity that is normally possessed by most compounds. 

There are now many other DNA synthesis inhibitors in use, e.g., cidofir, idoxuridine, famciclovir, ganciclovir, and trifluorothymidine, and this class of compound makes up the majority of antiviral agents currently available or in clinical trials. However poor selectivity (and the associated toxicity) is still a key problem in this area owing to the similarities of viral and cellular metabolism (5). 

Viruses are obligate intracellular organisms as their replication is based on DNA and RNA dependent processes and protein synthesis of the host. Antiviral therapy can therefore not be as selective as antibacterial treatments and anti-viral agents tend to inhibit host cell function and can cause major toxicity. An other problem with antiviral therapy is the fact that active viral replication mostly takes place before symptoms become manifest. Our armamentarium against most viral infections is limited. 

Comparative biochemical and antiviral studies are described for the 2 -fluoro-substituted arabinosyl-pyrimidine nucleosides l-(2 -deoxy-2 - luoro-p-D-arabinofuranosyl)-5-methyluraoil IFMAOl and l-(2 -deoiy-2 -fluoro-p-D-arabinofuranosyl)-5-ethyluracil [FEAU]. Biochemical studies indicated that FEAU should be a selective antiherpesvirus agent that is less toxic than FMAU. FEAU was evaluated against simian varicella virus infection in African green monkeys and, like FMAU. was highly effective in preventing rash and reducing viremia without apparent toxicity at doses of 30, 10, or 3 mg/kg/day x 10 administered intravenously. 

Nucleoside oc-Hydroxyphosphonates. In recent years, there has been a tremendous resurgence of interest in synthesis of modified nucleosides, primarily because of their potential antiviral activity. Three modified nucleosides, 3 -azidothymidine [210], dideoxyinosine [211], and dideoxycytidine [212], are the only drugs of recognized therapeutic value in the treatment of AIDS. Their toxic side effects [213], which limited the application of these compounds, are the driving force to develop new nucleoside derivatives with the potential to be more selective anti-HIV agents. 

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