Sialidases

Qlo Glycosidase (Glycoside hydrolase) Aminodeoxyglycosidase [Glycosaminidase] Glycosiduronase [Glycuronidase] Glyculosidonase [Neuraminidase] [Sialidase]... 

Anti-Influenza Drugs The Development of Sialidase Inhibitors... 

Further Developments of Influenza Virus Sialidase Inhibitors. 123... 

An overview of the role of the virus-associated glycoprotein sialidase (neuraminidase) and some of the most recent developments towards the discovery of anti-influenza drugs based on the inhibition of influenza virus sialidase is provided in this chapter. 

F%.2 A view of the influenza vims sialidase (NA) monomer with a-Neu5Ac 3a bound in the active site... 

Influenza virus sialidase (Fig. 2) is a tetrameric glycoprotein consisting of four identical subnnits (Colman and Ward 1985), and acts as a glycohydrolase that removes a-ketosidically linked terminal AT-acetylneuraminic acid residues from gly-coconjugates. 

The sialidase active site contains a relatively high number of charged amino acids and, in total, there are ten polar (Arg/Asp/Glu) and four non-polar residues that... 

Fig. 3 Sialidase inhibitor Neu5Ac2en 4 bound in the active site of influenza A virus sialidase (from PDB structure IfSb (Smith et al, 2001)), Left Stick model of 4 surrounded by some important active site residues. Right Electrostatic potential surface rendering of the active site (blue -positive, red - negative), (Amino acid numbering for influenza A/N2 sialidase is used throughout this review)...

Fig. 4 The influenza A viras sialidase active site showing some key interactions...

Scheme 1 The reaction catalyzed by influenza viras sialidase. The initially formed a-anomer 3a undergoes rapid equilibration with the 3-anomer 3b...

Neu5Ac2en 4, a micromolar inhibitor of influenza virus sialidase 4 x 10 M (A/N2)] (Holzer et al. 1993), was first identified as a very good inhibitor in the late 1960s (Meindl and Tuppy 1969). A series of C-5 modified Neu5Ac2en derivatives provided the first improved in vitro inhibitors compared with the parent compound 4. The replacement of the C-5 A-acetyl moiety with a A-trifluoroacetyl group resulted in the most potent inhibitor of this series, 2-deoxy-2,3-didehydro-A-trifluoroacetylneuraminic acid 10 [A] 8 x 10 M (A/Nl)] (Meindl et al. 1974). While these C-5 modified compounds were also very effective in cell culture assays (Palese et al. 1974a Palese and Compans 1976), none, including the parent... 

In the following sections, an overview of some of the key developments in the discovery of potent influenza vims sialidase inhibitors is provided. In the first instance, the discovery of the influenza vims sialidase inhibitors that have become the current first-hne-of-defence anti-influenza dmgs will be described, followed by a description of some of the other important sialidase inhibitor developments to date. 

Numbering used throughout reflects that reported for influenza virus A N2 sialidase. 

Fig. 5 Key interactions of 4-deoxy-4-guanidino-Neu5Ac2en (zanamivir) 12 with the active site of influenza A virus sialidase [Figure generated from crystal strucmre data (PDB - Innc) using LIGPLOT (Wallace et al. 1995)]. To the right is shown zanamivir 12 in the same orientation...

The discovery of the potent in vitro sialidase inhibitory activity and in vivo efficacy of zanamivir 12, and the increasing availability of 3D structural data for influenza virus sialidases in the 1990s, particularly with Neu5Ac and various inhibitors bound into the active site, provided a platform for further drug discovery efforts targeting... 

Analysis of Potential Binding Interactions within the Influenza Virus Sialidase Active Site... 

Fig. 7 The influenza virus A sialidase active site showing the five potential inhibitor binding subsites (with S5 containing the hydrophobic pocket formed by reorientation of the Glu276 side-chain), with oseltamivir carboxylate 18 placed in the active site...

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