Influenza A neuraminidase

Based on the lead compound BANA 113 42, which inhibits influenza A neuraminidase with a Ki of 2.5 p.M [91a,b], several novel 2-pyrrolidinone derivatives were designed. Whereas compound 43 (BANA 205) is a relatively weak inhibitor of influenza A and B neuraminidases, with IC50 values in the low micromolar range, compound 44 (BANA 206) is much more potent, with an IC50 value of 48 nM against influenza A neuraminidase. However, this compound is not as potent against influenza B virus sialidase [91d,e]. 

Interestingly, the comparison of the X-ray crystal structures of the complexes of influenza A neuraminidase with zanamivir 28 and BANA 113 42 revealed that, whUe the carboxylate and A-acetyl groups occupy the same subsites, the guanidino functionalities interact with the enzyme in different ways (Figure 16.14) [9Id]. 

Range of inhibitory potency against 15 different influenza A neuraminidases and 8 different influenza B neuraminidases... 

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We have already discussed one envelope protein of influenza virus, neuraminidase, as an example of an up-and-down antiparallel p motif. In the second envelope protein, hemagglutinin, one domain of the polypeptide chain is folded into a jelly roll motif. We shall now look at some other features of hemagglutinin that are important for its biological function. 

The second protein in the membrane of influenza vims, neuraminidase, does not belong to any of these three groups of barrel structures. Instead, it forms a propeller-like structure of 24 p strands, arranged in six similar motifs that form the six blades of the propeller. Each motif is a p sheet of 4 up-and-down-connected p strands. The enzyme active site is formed by loop regions on one side of the propeller. 

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Two neuraminidase inhibitors (oseltamivir carboxylate and zanamivir) are approved for prevention and treatment of infections with both influenza A and B viruses as discussed in chapter by Itzstein and Thomson, this volume. Oseltamivir carboxylate (OC) has gained most use because it can be taken orally, whereas the current formulation of zanamivir has to be inhaled. In addition, the WHO reconunends oseltamivir for treatment of clinically confirmed cases of H5N1 and for post-exposme prophylaxis to control recent H5N1 avian influenza outbreaks. 

The influenza virus possesses a neuraminidase that plays a key role in elution of newly synthesized progeny from infected cells. If this process is inhibited, spread of the vims is markedly diminished. Inhibitors of this enzyme are now available for use in treating patients with influenza. 

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