Selective toxicity antiviral drugs

In the case of antibiotic chemotherapy, the ideal pharmacodynamic response is usually no pharmacodynamic response the pharmacological target is not normal human cells but rather a parasite, a virus-infected human cell, or a cancerous cell. The less selective the chemotherapeutic drug, the greater the severity of adverse effects. Cancer chemotherapy is often severely toxic, even life threatening. Suppression of a viral infection, such as occurs in the treatment of HIV with antiviral drugs, is often complicated by serious drug-associated toxicity, such as hepatotoxicity or bone marrow suppression. 

Fig. 3. FACScan analysis of C8166 cells. C8166 cells infected with HIV-1, 4 d postinfection, were stained with (A) control FITC-conjugated isotype antibody, (B) ethidium monoazide bromide (EMA), (C) HIV-specific anti-p24 FITC-con-jugated MAb, and (D) dual stained with EMA and anti-p24-FITC. Dual staining allows determination of the proportion of cells that are either live or dead or infected or uninfected and hence the proportion of cells that are both dead and infected, dead and uninfected, live and infected, or live and uninfected. Comparison of the proportion of cells that are dead/live/infected/uninfected with potential antiviral drug-treated and untreated cells will give an indication of whether the drug is selectively toxic for virus-infected cells or cytotoxic regardless of infection. Data were acquired on a Becton Dickinson FACScan and analyzed using WinMDI software.

The mechanism of action of rifamycins involves primarily a strong, but noncovalent, interaction with DNA-dependent RNA polymerase enzyme in sensitive bacterial cells. The mammalian enzyme is not affected, which explains the selective toxicity neither is it mutated to resistant organisms. RNA polymerase has two components. The core enzyme contains polypeptide subunits a, J3, and i and a c factor, which are needed for recognition of RNA synthesis initiation sites. The drug binds to the J subunit of the complete enzyme only. The result is effective inhibition of RNA synthesis. It is of interest that many rifampinlike hydrazine derivatives were also found to be potent inhibitors of reverse transcriptase and shown to have antiviral properties. 

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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