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Strategies in the design of antiviral drugs

Key Points

  • Greater understanding of viral life cycles has resulted in the discovery and validation of several targets for therapeutic intervention, and an increase in the number of antiviral drugs from 5 in 1990 to over 30 in 2001. However, there is considerable room for improvement, as these compounds are not always efficacious (owing to virus resistance) or well tolerated.

  • Antiviral drug design could, in principle, be targeted at either viral proteins or cellular proteins. The first approach is likely to yield more specific, less toxic compounds, with a narrow spectrum of antiviral activity and a higher likelihood of resistance developing. The second approach might afford antiviral compounds with a broader activity spectrum and less chance of resistance developing, but higher likelihood of toxicity.

  • Some stages in the viral life cycle that can, or could, be targeted by drugs include virus adsorption, virus–cell fusion, viral DNA or RNA synthesis and viral enzymes, such as HIV protease and influenza virus neuraminidase. Two host cellular enzymes, inosine 5′-monophosphate dehydrogenase and S-adenosylhomocysteine hydrolase, could also be targets for certain classes of antiviral agents.

  • Licensed drugs include:

  • Inhibitors of viral DNA polymerases: nucleoside analogues such as acyclovir, and acyclic nucleoside phosphonates such as cidofovir.

  • Inhibitors of HIV reverse transcriptase: nucleoside reverse transcriptase inhibitors such as azidothymidine, non-nucleoside reverse transcriptase inhibitors such as nevirapine, and acyclic nucleoside phosphonates such as tenofovir and adefovir.

  • Inhibitors of HIV protease, such as indinavir.

  • Inhibitors of influenza virus neuraminidase, such as zanamivir.

  • IMP dehydrogenase inhibitors, such as ribavirin and mycophenolic acid.

  • Drugs in development that are not in the above classes include:

  • Inhibitors of virus adsorption, such as polyanions.

  • Inhibitors of virus–cell fusion, such as AMD3100, TAK779 and T20.

  • Inhibitors of human rhinovirus proteases, such as AG7088.

Abstract

A decade ago, just five drugs were licensed for the treatment of viral infections. Since then, greater understanding of viral life cycles, prompted in particular by the need to combat human immunodeficiency virus, has resulted in the discovery and validation of several targets for therapeutic intervention. Consequently, the current antiviral repertoire now includes more than 30 drugs. But we still lack effective therapies for several viral infections, and established treatments are not always effective or well tolerated, highlighting the need for further refinement of antiviral drug design and development. Here, I describe the rationale behind current and future drug-based strategies for combating viral infections.

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Figure 1: The viral life cycle, as exemplified by HIV.
Figure 2: Basic (skeletal) pharmacophores or prototypic compounds of the classes of antiviral agents described in this review.
Figure 3: Interaction of CCR5 with TAK779.
Figure 4: Examples of antiviral nucleoside analogues acting by a chain termination mechanism.
Figure 5: Interaction of HIV-1 RT with UC781.
Figure 6: Interaction of HIV protease with KNI272.
Figure 7: Interaction of influenza neuraminidase with oseltamivir.

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Acknowledgements

E.D.C. holds the Professor P. De Somer Chair of Microbiology at the School of Medicine, Katholieke Universiteit Leuven, Belgium, and thanks C. Callebaut for her invaluable editorial assistance.

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DATABASES

LocusLink

CCR5

CDK9

CXCR4

IMP dehydrogenase

interferon-α

MIP1

NF-κB

RANTES

SAH hydrolase

SDF1

Medscape DrugInfo

abacavir

acyclovir

amprenavir

cidofovir

delavirdine

didanosine

efavirnez

famciclovir

ganciclovir

indinavir

lamivudine

lopinavir

nelfinavir

nevirapine

oseltamivir

penciclovir

ribavirin

ritonavir

saquinavir

stavudine

valaciclovir

valganciclovir

zanamivir

zalcitabine

zidovudine

Protein Data Bank

GS4071

IMP dehydrogenase

NS3 helicase

NS5B

FURTHER INFORMATION

Encyclopedia of Life Sciences

Antiviral drugs

Glossary

VIRION

A mature infectious virus particle.

V3 LOOP

The gp120 protein has eleven defined loop segments, five of which are termed variable (designated V1–V5).

ENVELOPE

A lipoprotein-bilayer outer membrane of many viruses. Envelope proteins often aid in identifying and attaching the virus to a cell-surface receptor, whereby viral entry can occur.

PRODRUG

A pharmacologically inactive compound that is converted to the active form of the drug by endogenous enzymes or metabolism. It is generally designed to overcome problems associated with stability, toxicity, lack of specificity or limited (oral) bioavailability.

CONGENER

Any member of the same chemical family.

ALLOSTERIC SITES

Two or more topologically distinct binding sites within a protein can interact functionally with each other. So, two sites in different positions can bind ligands (substrates, inhibitors and so on), and binding of a ligand at one site alters the properties of the other(s).

CPK COLOURING

The CPK colour scheme for elements is based on the colours of the popular plastic space-filling models developed by Corey, Pauling and Kultun, and is conventionally used by chemists. In this scheme, carbon is represented in light grey, oxygen in red, nitrogen in blue, sulphur in yellow, hydrogen in white and chlorine in green.

SEROTYPE

Variety of a species (usually bacteria or virus) characterized by its antigenic properties.

PEGYLATION

Addition of poly(ethylene glycol) (PEG) groups to proteins can increase their resistance to proteolytic degradation, improve their water solubility and reduce their antigenicity.

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De Clercq, E. Strategies in the design of antiviral drugs. Nat Rev Drug Discov 1, 13–25 (2002). https://doi.org/10.1038/nrd703

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  • DOI: https://doi.org/10.1038/nrd703

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