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Chapter 11 : Influenza Virus Antiviral Targets

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Abstract:

Influenza viruses are classified as type A, B, or C based on antigenic reactions of their internal proteins. Type A influenza viruses are further divided into subtypes according to the antigenic properties of their surface antigens, the glycoproteins hemagglutinin (HA) and neuraminidase (NA). The genome of influenza virus consists of eight segments of single-stranded RNA, ranging in size from ~900 to 2,300 nucleotides. Each RNA segment contains the coding information for one or two proteins, but in the negative sense. The RNA segments are coated with the nucleoprotein (NP), and some are associated with the three subunits of the viral RNA-dependent RNA polymerase complex. The chapter discusses targets for antivirals against influenza. The M2 ion channel is the target of the earliest licensed antiviral drugs against influenza, amantadine and rimantadine. NA is the second most abundant glycoprotein on the virus surface. It cleaves sialic acid residues from glycoproteins and some glycolipids, thus acting as a receptordestroying activity. The cyclopentane peramivir was developed by BioCryst, again based on the crystal structure of NA and its interactions with inhibitors. The aim was to find an inhibitor that was readily synthesized and orally available and that did not induce resistance. The chapter talks about development of antiviral drugs targeted to influenza, and targeting host functions. The diversity of influenza viruses and their capacity to change present a particular challenge to the development and use of anti-influenza antivirals.

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11
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Figures

Image of Figure 1.
Figure 1.

Structure and functions of the polymerase trimer. (A) Location of active sites on the polymerase trimer. C, cap-binding; E, endonuclease; 3’, binding site for 3’ end of template RNA; 5’, binding site for 5’ end of template RNA; pol, polymerase active site. The figure has been composed using information from references , and . No specific functions have yet been mapped to the PA subunit, which interacts with PB1 but apparently not to PB2 ( ). (B) Chimeric model using the three-dimensional reconstruction of a short RNP ( ) docked to a three-dimensional reconstruction of the polymerase trimer ( ). Reproduced from reference with permission.

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11
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Image of Figure 2.
Figure 2.

Amantadine and rimantadine.

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11
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Image of Figure 3.
Figure 3.

Structures of NA inhibitors.

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11
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Image of Figure 4.
Figure 4.

Administration of Relenza. Instructions from GlaxoSmithKline are available at http://www.relenza.com/inhaler-step-by-step.html.

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11
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Image of Figure 5.
Figure 5.

Inhibitors of the influenza polymerase and endonuclease activities.

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11
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Tables

Generic image for table
Table 1.

Functions of NS1, with various subsets shown by individual influenza A and B viruses

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11
Generic image for table
Table 2.

Mutations inducing resistance to NA inhibitors

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11

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