Nucleoside analogue predecessors of aciclovir such as idoxuridine (IDU) and trifluorothymidine (TFT) were useful for treating superficial herpes infections (including those of the eye), whilst adenine arabinoside (ara A) had an important and pioneering role in the treatment of herpes encephalitis and serious paediatric infections. However, the advent of aciclovir transformed the often difficult clinical management of herpetic infections and these earlier discovered drugs, with the possible exception of TFT, are no longer used. Aciclovir is used as a prophylactic, before surgery for example, to prevent recurrent herpes type I infections in bone marrow and heart transplant patients, and therapeutically to prevent spread of mucocutaneous infections in already infected and immune compromised persons. It has also been shown to be very effective in saving lives when used to treat herpes encephalitis. Aciclovir is also used against recurrent HSV infections, particularly those of the genital tract, and to a lesser extent in various forms of VZV infections. Actually there is an urgent need for highly active drugs against VZV and this infection will come even more to the public's notice as the population ages. More effective against VZV is the prodrug of aciclovir, valaciclovir which is better absorbed orally and is rapidly converted to aciclovir in vivo.
A molecular relative ganciclovir, has antiviral activity against cyto-megalovirus (CMV) and is used to treat life-threatening CMV infections after bone marrow transplants, or CMV pneumonia or retinitis in AIDS patients. However, unlike aciclovir the drug induces rather severe neutropenia and thrombocytopenia. Although CMV does not have a viral TK enzyme, another viral protein phosphorylates ganciclovir to the monophosphate and thereafter a cellular enzyme phosphorylates the molecule to ganciclovir triphosphate, which inhibits CMV DNA polymerase.
Foscarnet, which is not a nucleoside analogue, can be used to treat intractable cases of CMV but the drug is administered in hospitals under close clinical care.
Aciclovir possesses an excellent combination of pharmacological and antiviral properties which helps to explain its unique and highly specific anti-herpesvirus specificity. Firstly, the compound is only phosphorylated in herpes-infected cells, since the herpes thymidine kinase enzyme is less 'precise' than the corresponding cellular enzyme and will accept fraudulent substrates, such as aciclovir. This means that any potential drug-induced toxicity is immediately avoided or at least confined to a virus infected cell. Once phosphorylated to the triphosphate by cellular enzymes the latter molecule inhibits, again specifically, the function of the herpesvirus DNA polymerase and has no effect on cellular DNA polymerases. It is both an inhibitor and a substrate of viral DNA polymerase competing with GTP and being incorporated into viral DNA. It has little or no effect against cellular DNA polymerase. New herpes DNA elongation is aborted very successfully because aciclovir lacks the 3' hydroxyl group on the sugar ring required for phosphate-sugar linkage and hence addition of new bases and hence DNA chain elongation.
However, a latently infected cell cannot be cured and thus aciclovir does not eradicate herpesvirus from an infected individual, but it can be used to prevent clinical recurrences. The compound has proved to be remarkably safe in clinical practice and some patients have taken the drug orally (daily) for several years. In fact in several countries in the European Community, aciclovir can be purchased as an 'over-the-counter' drug for self-prescription for cutaneous HSV infection, as with cold sores around the mouth.
Another nucleoside analogue closely related to aciclovir and called penciclovir is widely used in clinical practice, with an advantage that fewer daily doses are required. As with the prodrug valaciclovir, a prodrug of the new molecule has been introduced called famciclovir (Figure 4.4). This prodrug may also have clinical usefulness against hepatitis B virus.
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