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Antiherpesvirus drugs: a promising spectrum of new drugs and drug targets

Nature Reviews Drug Discovery volume 2, pages 278–288 (2003)Cite this article

Key Points

  • Herpesviruses cause a variety of important diseases. Although the current mainstays of antiherpesvirus therapies — nucleoside analogues — have been successful by many criteria, they have numerous drawbacks, including the emergence of resistant viruses, which motivate the development of new antiherpesvirus drugs.

  • Drugs that target different stages of herpesvirus replication are under development. Drugs that target viral attachment and entry would be especially attractive, and new information about this stage of virus infection might identify new therapeutic targets.

  • Drugs that target herpesvirus gene expression have been identified, but their mechanisms of action remain poorly understood.

  • Several different classes of drugs target herpesvirus DNA replication. Some of these — including non-nucleoside inhibitors of viral DNA polymerase and helicase–primase inhibitors — show considerable promise and could soon enter human trials.

  • New inhibitors of herpesvirus assembly, encapsidation and nuclear egress have been developed. These compounds target different aspects of this late stage of infection, and several have entered clinical trials.

  • Strategies to inhibit herpesvirus replication by interfering with host-cell processes have been developed. These strategies include the inhibition of cyclin-dependent kinases and of cyclooxygenase-2.

  • No presently licensed antiviral drug is active against latent herpesvirus infections, so no cure for these infections is in sight. However, potential therapeutic targets have been identified in studies of Epstein–Barr virus proteins expressed during latency. These studies suggest strategies that might eventually be fruitful against latent infections.

Abstract

In the absence of effective vaccines to control herpesvirus infections, nucleosidic antiviral drugs have been the mainstay of clinical treatment since their development in the late 1970s. However, given the drawbacks of these drugs, including the increasing emergence of drug-resistant clinical isolates, new strategies for treating herpesvirus infections are warranted. A range of promising new drugs with novel molecular targets has been developed, but will they cure latent infections?

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Figure 1: Herpesvirus replication cycle.
Figure 2: Herpesvirus DNA replication.
Figure 3: Inhibitors of herpesvirus DNA replication.
Figure 4: Possible inhibitors of herpesvirus gene expression.
Figure 5: Inhibitors of herpesvirus assembly, encapsidation and nuclear egress.
Figure 6: Inhibitors of cellular proteins that block viral replication.

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Authors and Affiliations

  1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, 02115, Massachussets, USA

    Donald M. Coen

  2. Department of Medicine and Department of Microbiology and Molecular Genetics, Harvard Medical School at the Beth Israel Deaconess Medical Center, Boston, 02215, Massachussets, USA

    Priscilla A. Schaffer

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  1. Donald M. Coen
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DATABASES

LocusLink

COX2

Thymidine kinase

FURTHER INFORMATION

Encyclopedia of Life Sciences

Antiviral drugs

Epstein–Barr virus

Herpesvirus (human)

cytomegaloviruses

cytomegalovirus in human infection

Glossary

NUCLEOSIDE ANALOGUES

Compounds that resemble nucleosides.

DNA POLYMERASE

An enzyme that extends RNA or DNA primer chains in a template-dependent fashion by incorporating deoxynucleoside triphosphates.

PRODRUG

A compound that is subsequently converted into the actual drug once administered

KINASE

An enzyme that adds phosphate groups to its substrates.

HELICASE

An enzyme that unwinds DNA at the replication fork.

PRIMASE

An enzyme that synthesizes short RNA primers that are subsequently elongated by DNA polymerase.

RIBONUCLEOTIDE REDUCTASE

An enzyme that converts ribnucleoside diphosphates into deoxyribonucleoside diphosphates.

PEPTIDOMIMETICS

Non-peptidic compounds that mimic peptides.

ENCAPSIDATION

An event during viral assembly in which the viral nucleic acid becomes surrounded by the protein capsid.

CLEAVAGE

An event during the assembly of certain viruses in which long nucleic-acid precursors are cleaved to the correct length during the encapsidation process.

TERMINASE

An enzyme that cleaves DNA during the encapsidation process.

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Coen, D., Schaffer, P. Antiherpesvirus drugs: a promising spectrum of new drugs and drug targets. Nat Rev Drug Discov 2, 278–288 (2003). https://doi.org/10.1038/nrd1065

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