Chapter 13 : Antiviral Treatment of Flaviviruses

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This chapter discusses the key question of unavailability approved antiviral treatments for flavivirus pathogens which cause significant morbidity and mortality, examines the progress made in the development of therapies, identifies key targets of therapy, and reviews the challenges to overcome in the development of antiflaviviral disease treatments. It deals only with members of the genus, which include viruses of human concern, such as dengue virus (DV), yellow fever virus (YFV), West Nile virus (WNV), Japanese encephalitis virus (JEV), Murray Valley encephalitis virus (MVEV), Saint Louis encephalitis virus (SLEV), and tick-borne encephalitis virus (TBEV), all of which cause morbidity and mortality. A few flaviviruses, primarily DV and YFV, cause hemorrhagic manifestations in severe infection. The chapter investigates targets for the treatment of flaviviruses, including viral and host elements that may be effectively targeted for treatment. Important progress in the treatment of flavivirus infections has been made recently, bringing ever closer to fruition the important goal of developing a broad-spectrum agent that is effective after disease manifestation. New animal models of flaviviral disease would be important in developing a better understanding of basic virology and antiviral treatment. Epidemiological methods to detect and predict the severity and location of outbreaks would be beneficial in control of DV diseases, giving better chances to efficacy of antiflaviviral agents. Alerting physicians or veterinarians of emerging flaviviral outbreaks would also help improve the diagnosis and treatment of human or animal infections.

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
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Image of Figure 1.
Figure 1.

Key points of virus replication in regard to antiviral treatment are numbered in this outline of the flavivirus life cycle: 1, the virus attaches to the membrane of a host cell; 2, the virus enters the cell via endocytosis; 3, the endocytotic vesicle fuses with a lysosome, after which the virus is released into the cytoplasm; 4, viral RNA is released; 5, the positive-strand [(+)-strand] RNA genome is translated into a polyprotein by host cell machinery; 6, the polyprotein is cleaved by cellular and viral proteases; 7, viral enzymes replicate the viral RNA; 8, the viral RNA associates with NS proteins during assembly; 9, virus then may bud into the endoplasmic reticulum (ER); 10, virus matures and is released from the cell.

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
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Image of Figure 2.
Figure 2.

Diagrammatical representation of a typical flavivirus polyprotein. The 5’ end of the genome has a cap structure followed by an untranslated region (UTR). The genes coding for structural proteins, including nucleocapsid (C), Pre-M, and E, are located at the 5’ end of the coding region. NS proteins make up the last part of the coding sequence, followed by a 3’ UTR.

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
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Image of Figure 3.
Figure 3.

Structures of the DV (A) and WNV (B) NS5 polymerase proteins.

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
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Image of Figure 4.
Figure 4.

Chemical structures of T-1106 and T-705.

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
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Image of Figure 5.
Figure 5.

Chemical structure of ribavirin.

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
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Image of Figure 6.
Figure 6.

Structure of the NS3 protease protein of DV.

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
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Image of Figure 7.
Figure 7.

Helicase proteins from DV (A) and YFV (B).

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
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Image of Figure 8.
Figure 8.

E proteins from DV (A) and WNV (B).

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
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Generic image for table
Table 1.

Cases of WNV disease reported in the United States from 1999 through 25 September 2007

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
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Table 2.

Compounds efficacious in the treatment of flaviviruses in various cell culture models

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
Generic image for table
Table 3.

Select compounds with activity against flaviviruses in various animal models of disease

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13

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