triphosphate form, aciclo-GTP, by cellular kinases. Mechanism of action Aciclo-GTP, the active triphosphate metabolite of aciclovir, is a very potent inhibitor of viral DNA replication. Aciclo-GTP competitively inhibits and inactivates the viral DNA polymerase. Its monophosphate form also incorporates into the viral DNA, resulting in chain termination. It has also been shown that the viral enzymes cannot remove aciclo-GMP from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolized within the cell, possibly by cellular phosphatases. Aciclovir is active against most species in the herpesvirus family. In descending order of activity: Herpes simplex virus type I (HSV-1) Herpes simplex virus type II (HSV-2) Varicella zoster virus (VZV) Epstein–Barr virus (EBV) Cytomegalovirus (CMV) The drug is predominantly active against HSV and, to a lesser extent, VZV. It is only of limited efficacy against EBV and CMV. However, valaciclovir has been shown to lower or eliminate the presence of the Epstein–Barr virus in subjects afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms. Valaciclovir and acyclovir act by inhibiting viral DNA replication, but as of 2016 there was little evidence that they are effective against Epstein–Barr virus, they are expensive, they risk causing resistance to antiviral agents, and (in 1% to 10% of cases) can cause unpleasant side effects. Acyclovir therapy does prevent viral latency, but has not proven effective at eradicating latent viruses in nerve ganglia. As of 2005, resistance to valaciclovir has not been significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase and mutations to viral thymidine kinase and/or DNA polymerase that alter substrate sensitivity. It also is used for herpes B virus postexposure prophylaxis. Chemistry Details of the synthesis of valaciclovir were first published by scientists from the Wellcome Foundation. Aciclovir was esterified with a carboxybenzyl protected valine, using dicyclohexylcarbodiimide as the dehydrating agent. In the final step, the protecting group was removed by hydrogenation using a palladium on alumina catalyst. History Valaciclovir was patented in 1987 and came into medical use in 1995. It is available as a generic medication. In 2019, it was the 110th most commonly prescribed medication in the United States, with more than 5million prescriptions. Society and culture Brand names It is marketed by GlaxoSmithKline under the brand names Valtrex and Zelitrex. Valaciclovir has been available as a generic drug in the U.S. since November 2009. References External