A broad inhibitor of viral DNA polymerases---Foscarnet

Foscarnet, also known as phosphonoformate, is an organic analog of inorganic pyrophosphate. Foscarnet is a broad inhibitor of viral DNA polymerases, including both DNA-dependent and RNA-dependent DNA polymerases (the latter usually called reverse transcriptases). It is active against the DNA viruses herpes simplex virus types 1 and 2, cytomegalovirus (CMV), varicella-zoster virus, Epstein–Barr virus, and human herpesviruses types 6 and 8. In addition, it inhibits the reverse transcriptases of hepadnaviruses, including human hepatitis B viruses and primate immunodeficiency viruses, such as HIV-1. It also interferes with mRNA synthesis of influenza viruses. 

PHARMACOKINETICS

Clinically, it is used to treat herpesvirus infections, especially those resistant to the usual antiviral drugs and, rarely, for treatment of multidrug-resistant HIV infection. The chemical name for foscarnet is trisodium phosphonoformate hexahydrate and it is marketed by AstraZeneca under the brand name Foscavirs. Foscarnet is available for intravenous injection as water, pH 7.4, with 24 mg of trisodium phosphonoformate hexahydrate per ml. Foscarnet is available for intravenous infusion (Foscavir injection) in 500-ml glass bottles (each ml of the pH 7.4 solution contains 24 mg (80 mM) foscarnet). Prodrugs of foscarnet have been synthesized in an effort to increase oral absorption and tolerability, but they have not been studied clinically, and a liposomal preparation for intraocular use has been developed, but also has not undergone clinical trials.

MECHANISM OF DRUG ACTION 

Foscarnet inhibits the DNA polymerases (both DNA-dependent and RNA-dependent, the latter usually called reverse transcriptases) of several virus families. Unlike nucleoside and nucleotide antiviral drugs, foscarnet does not require intracellular alteration for its activity. 

Foscarnet inhibits the DNA polymerase of herpesviruses by binding at a site where pyrophosphate is removed as the DNA chain grows by addition of nucleoside triphosphates. Addition of a deoxynucleoside triphosphate to the growing DNA chain releases a pyrophosphate during this process. Foscarnet selectively inhibits the viral DNA polymerase, without significantly inhibiting cellular enzymes. Similarly, foscarnet inhibits the reverse transcriptase of the human immunodeficiency virus and of hepadnaviruses. Inhibition is reversed when infected cells are no longer exposed to the compound. 

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