14.4 Mechanisms of other antimicrobial drugs  (Page 8/15)

Neuraminidase inhibitors, including olsetamivir ( Tamiflu ), zanamivir ( Relenza ), and peramivir ( Rapivab ), specifically target influenza viruses by blocking the activity of influenza virus neuraminidase , preventing the release of the virus from infected cells. These three antivirals can decrease flu symptoms and shorten the duration of illness, but they differ in their modes of administration: olsetamivir is administered orally, zanamivir is inhaled, and peramivir is administered intravenously. Resistance to these neuraminidase inhibitors still seems to be minimal.

Pleconaril is a synthetic antiviral under development that showed promise for the treatment of picornaviruses . Use of pleconaril for the treatment of the common cold caused by rhinoviruses was not approved by the FDA in 2002 because of lack of proven effectiveness, lack of stability, and association with irregular menstruation. Its further development for this purpose was halted in 2007. However, pleconaril is still being investigated for use in the treatment of life-threatening complications of enteroviruses , such as meningitis and sepsis . It is also being investigated for use in the global eradication of a specific enterovirus, polio . M.J. Abzug. “The Enteroviruses: Problems in Need of Treatments.” Journal of Infection 68 no. S1 (2014):108–14. Pleconaril seems to work by binding to the viral capsid and preventing the uncoating of viral particles inside host cells during viral infection.

Viruses with complex life cycles, such as HIV , can be more difficult to treat. First, HIV targets CD4-positive white blood cells, which are necessary for a normal immune response to infection. Second, HIV is a retrovirus , meaning that it converts its RNA genome into a DNA copy that integrates into the host cell’s genome, thus hiding within host cell DNA. Third, the HIV reverse transcriptase lacks proofreading activity and introduces mutations that allow for rapid development of antiviral drug resistance. To help prevent the emergence of resistance, a combination of specific synthetic antiviral drugs is typically used in ART for HIV ( [link] ).

The reverse transcriptase inhibitors block the early step of converting viral RNA genome into DNA, and can include competitive nucleoside analog inhibitors (e.g., azidothymidine/zidovudine , or AZT) and non-nucleoside noncompetitive inhibitors (e.g., etravirine ) that bind reverse transcriptase and cause an inactivating conformational change. Drugs called protease inhibitors (e.g., ritonavir ) block the processing of viral proteins and prevent viral maturation. Protease inhibitors are also being developed for the treatment of other viral types. B.L. Pearlman. “Protease Inhibitors for the Treatment of Chronic Hepatitis C Genotype-1 Infection: The New Standard of Care.” Lancet Infectious Diseases 12 no. 9 (2012):717–728. For example, simeprevir ( Olysio ) has been approved for the treatment of hepatitis C and is administered with ribavirin and interferon in combination therapy. The integrase inhibitors (e.g., raltegravir ), block the activity of the HIV integrase responsible for the recombination of a DNA copy of the viral genome into the host cell chromosome. Additional drug classes for HIV treatment include the CCR5 antagonists and the fusion inhibitors (e.g., enfuviritide ), which prevent the binding of HIV to the host cell coreceptor (chemokine receptor type 5 [CCR5]) and the merging of the viral envelope with the host cell membrane, respectively. [link] shows the various therapeutic classes of antiviral drugs, categorized by mode of action, with examples of each.