Antiviral agents active against influenza A viruses

Abstract

The recent outbreaks of avian influenza A (H5N1) virus, its expanding geographic distribution and its ability to transfer to humans and cause severe infection have raised serious concerns about the measures available to control an avian or human pandemic of influenza A. In anticipation of such a pandemic, several preventive and therapeutic strategies have been proposed, including the stockpiling of antiviral drugs, in particular the neuraminidase inhibitors oseltamivir (Tamiflu; Roche) and zanamivir (Relenza; GlaxoSmithKline). This article reviews agents that have been shown to have activity against influenza A viruses and discusses their therapeutic potential, and also describes emerging strategies for targeting these viruses.

Figure 1. The two mechanisms by which pandemic influenza originates.

In 1918, the 'Spanish influenza' H1N1 virus, closely related to an avian virus, adapted to replicate efficiently in humans. In 1957 and 1968, reassortment events led to, respectively, the 'Asian influenza' H2N2 virus and the 'Hong Kong influenza' H3N2 virus. The 'Asian influenza' H2N2 virus acquired three genetic segments from an avian species (a haemagglutinin (H), a neuraminidase (N) and a polymerase (PB1) gene). The 'Hong Kong influenza' H3N2 virus acquired two genetic segments from an avian species (H and PB1). Future pandemic strains could arise through either mechanism. Figure adapted, with permission, from Ref. © (2005) Massachusetts Medical Society.

Figure 2. Inhibition of the influenza-virus replication cycle by antiviral agents.

After binding to sialic-acid receptors, influenza virions are internalized by receptor-mediated endocytosis. The low pH in the endosome triggers the fusion of viral and endosomal membranes, and the influx of H⁺ ions through the M2 channel releases the viral RNA genes in the cytoplasm. Adamantan(amin)e derivatives block this uncoating step. RNA replication and transcription occur in the nucleus. This process can be blocked by inhibitors of inosine 5′-monophosphate (IMP) dehydrogenase (a cellular enzyme) or viral RNA polymerase. The stability of the viral mRNA and its translation to viral protein might be prevented by small interfering RNAs (siRNAs). Packaging and budding of virions occur at the cytoplasmic membrane. Neuraminidase (N) inhibitors block the release of the newly formed virions from the infected cells. Figure adapted with permission from Ref. © (2004) Macmillan Magazines Ltd. H, haemagglutinin.

Figure 3. Adamantan(amin)e derivatives as antiviral drugs.

a | Amantadine, rimantadine and adamantanamine derivatives share several common structural features which relate to their mode of action: blockade of the M2 channel, which is responsible for transporting H⁺ ions (protons) into the interior of the virions and initiating the viral uncoating process (Fig. 2). The figure shows a model of the proposed transmembrane domain of the M2 protein with a top view as seen from the extracellular side and a cross-section in the plane of the lipid layer. Residues which were identified as facing the ion-conducting aqueous pore are indicated. b | Structures of the adamantan(amin)e derivatives amantadine and rimantadine, and various new adamantanamine derivatives: spiro[cyclopropane-1,2′-adamantan]-2-amine, spiro[pyrrolidine-2,2′-adamantane], spiro[piperidine-2,2′-adamantane], 2-(2-adamantyl)piperidine, 3-(2-adamantyl)pyrrolidine, rimantadine 2-isomers, 2-(1-adamantyl)piperidine, 2-(1-adamantyl)pyrrolidine and 2-(1-adamantyl)-2-methyl-pyrrolidine. Panel a reproduced with permission from Ref. © (2000) American Society for Microbiology.

Figure 4. Viral neuraminidase inhibition.

a | The neuraminidase cleaves off sialic acid (SA, also known as N-acetylneuraminic acid or NANA) from the cell receptor for influenza virus (b), so that the newly formed virus particles can be released from the cells. Neuraminidase inhibitors, such as zanamivir and oseltamivir (Fig. 5), interfere with the release of progeny influenza virions from the surface of infected host cells. In doing so, the neuraminidase inhibitors prevent virus infection of new host cells and thereby halt the spread of infection in the respiratory tract. b | SA linked to galactose (Gal) by an α2–3 linkage (SAα2–3Gal) or α2–6 linkage (SAα2–6Gal). Galactose is linked to N-acetylglucosamine (GlcNAc) through a β1–4 linkage. Panel a adapted with permission from Ref. © (2005) Massachusetts Medical Society.

Figure 5. Neuraminidase inhibitors.

a | Structures of DANA, FANA, zanamivir (4-guanidino-Neu5Ac2en, GG167), oseltamivir (GS4071 ethyl ester, GS4104, Ro64-0796), peramivir (RWJ-270201), cyclopentane derivatives, a cyclopentane amide derivative and pyrrolidine derivatives (A-192558 and A-315675). b | GS4071 within the active site of the influenza A viral neuraminidase. c | Locations of oseltamivir-resistance mutations (H274Y) showing that the tyrosine at position 252 is involved in a network of hydrogen bonds in group-1 (H5N1 and H1N1) neuraminidases. Panel b reproduced with permission from Ref. © (1997) American Chemical Society and Ref. © (2002) Macmillan Magazines Ltd. Panel c reproduced with permission from Ref. © (2006) Macmillan Magazines Ltd.

Figure 6. IMP dehydrogenase inhibition.

Viramidine acts as a prodrug (precursor) of ribavirin, which is converted intracellularly to its 5′-monophosphate derivative, ribavirin-MP. The latter inhibits inosine 5′-monophosphate (IMP) dehydrogenase, a crucial enzyme in the biosynthesis of RNA, including viral RNA. IMP dehydrogenase is responsible for the conversion of IMP into xanthosine 5′-monophosphate (XMP) which, in turn, is further converted to GMP (guanosine 5′-monophosphate), GDP (guanosine 5′-diphosphate) and GTP (guanosine 5′-triphosphate). The latter serves as substrate, together with ATP, UTP and CTP, in the synthesis of RNA.

Figure 7. Influenza-virus RNA-polymerase inhibitors.

a | FdG, Flutimide, thiadiazolo [2,3-a]pyrimidine and pyrimidinyl acylthiourea. b | The postulated mode of action of T-705, according to Furuta and colleagues.