from Part VI - Antiviral therapy
Published online by Cambridge University Press: 24 December 2009
Introduction
The remit of this chapter is to summarize what is known about licensed antiviral drugs for CMV. In summary, we do not possess a single anti-CMV drug, which is potent and safe enough to be given to all individuals infected with this virus. What follows therefore, is the evidence-base for prescribing the existing compounds with the objective of maximizing therapeutic efficacy and cost-effectiveness while minimizing toxicity.
Licensed drugs and mechanism of action
Nucleosides
Ganciclovir (GCV) and acyclovir (ACV) are related nucleosides (see Fig. 66.1) which are anabolized by a common cellular pathway. After activation, they are competitive inhibitors of CMV encoded DNA polymerase. In cells infected with CMV, the first stage of phosphorylation is achieved by the UL97 protein kinase. Once GCV is mono-phosphorylated within the virus-infected cell, it is charged and so unable to diffuse out of the cell. A concentration gradient is thereby formed across the plasma membrane, aiding diffusion of more GCV into the infected cell. Cellular enzymes convert GCV monophosphate to the triphosphate. GCV triphosphate is a potent inhibitor of CMV DNA polymerase and has a long intracellular half-life. Selectivity for virus-infected cells is achieved both by UL97 activation and because GCV triphosphate is a better inhibitor of CMV-encoded DNA polymerase than cellular DNA polymerase.
Ganciclovir possesses a free hydroxyl at a position equivalent to the 3' of the open sugar ring and so can allow DNA elongation.
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