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66 - Antiviral therapy for human cytomegalovirus

from Part VI - Antiviral therapy

Published online by Cambridge University Press:  24 December 2009

By
Paul D. Griffiths  and
Michael Boeckh
Edited by
Ann Arvin ,
Gabriella Campadelli-Fiume ,
Edward Mocarski ,
Patrick S. Moore ,
Bernard Roizman ,
Richard Whitley  and
Koichi Yamanishi
Paul D. Griffiths
Affiliation:
Royal Free and University College Medical School, London, UK
Michael Boeckh
Affiliation:
Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Ann Arvin
Affiliation:
Stanford University, California
Gabriella Campadelli-Fiume
Affiliation:
Università degli Studi, Bologna, Italy
Edward Mocarski
Affiliation:
Emory University, Atlanta
Patrick S. Moore
Affiliation:
University of Pittsburgh
Bernard Roizman
Affiliation:
University of Chicago
Richard Whitley
Affiliation:
University of Alabama, Birmingham
Koichi Yamanishi
Affiliation:
University of Osaka, Japan
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Summary

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.

Type
Chapter
Information
Human Herpesviruses
Biology, Therapy, and Immunoprophylaxis
 , pp. 1192 - 1210
Publisher: Cambridge University Press
Print publication year: 2007

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