Flu Virus Role of NA

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Influenza remains a major cause of mortality and morbidity worldwide. Vaccination affords some protection but must be reformulated each year based on a prediction of the most likely strains circulating in the coming flu season. The antigenic drift and shift characteristic of the virus limits the effectiveness of the vaccine, and some warn of a re-emergence of a catastrophic pandemic strain such as occurred in 1918— the so called Spanish flu [1]. Two antiviral drugs (amantadine and rimantadine) have existed for some time that target the viral ion-channel protein M2 [2], but these are ineffective against the type B influenza virus and cause unwanted side effects. Of the several influenza virus proteins, the surface glycoprotein neuraminidase (NA) has emerged as the most successful target for antiviral development, although other work has been carried out on the hemagglutinin (HA) [3,4] and endonuclease [5].

The influenza virus NA exists as a mushroom-shaped tetramer on the surface of the virus; a typical virus carries around 100 copies of NA and 400 copies of the other surface glycoprotein HA. HA contains domains that recognize sialic acid receptors (Neu5Ac, NANA) (Fig. 1, structure 1), the very sugar that NA hydrolyzes. NA catalyzes the cleavage of the a-ketosidic linkage between sialic acid and the adjacent sugar residue, which lowers membrane viscosity and permits entry of the virus into epithelial cells. NA also destroys the HA receptor on host cells, allowing the emergence of progeny virions from infected cells and presumably also removing sialic acid from the HA and NA of such virions to permit cell-to-cell spread of the virus [6,7]. Inhibitors of NA can therefore reduce this spread of the virus from the site of infection.

The first inhibitors were made in the 1960s through an attempt to understand the catalytic mechanism, which resulted in analogs of 2,3-didehydro-2-deoxy-N-acetylneuraminic acid (Neu5Ac2en, DANA) (Fig. 1, structure 2a) [8,9]. These compounds inhibited influenza virus NA with a K« 4 ||M, as they do most neuraminidases found in nature. Neuraminidases, or sialidases, are found in many pathogenic and nonpatho-genic bacteria, where they are largely secreted and provide primarily a nutritional role, although in the case of Vibrio cholerae, for example, the enzyme plays a defined role in pathogenesis [10-12]. Animals possess neuraminidases (three are encoded in the human genome) identified by characteristic sequence fingerprints (the so-called bacterial neuraminidase repeats, or BNRs) not found in the viral enzyme [12]. Certain parasites possess the enzyme GPI-linked to their surface, and in the case of Trypanosoma cruzi the enzyme

Figure 1 Influenza virus NA ligands.

serves as a more efficient trans-sialidase rather than a sialidase [13,14]. Finally, paramyxoviruses possess surface glycoproteins (HNs), which embody the functions of both hemagglutinin and neuraminidase and appear to have a combined, single sialic acid recognition site [15-17]. Any influenza virus inhibitors must therefore avoid inhibiting the endogenous human enzymes which play key roles in modulating cell-surface sialic acid in events from immune response to apoptosis [17,18].

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