Sialidase 150-cavity

Application of sialidase inhibitors for medical use is still in a premature state. It is imaginable that inhibitors would be useful drugs in infections, caused by micro-organisms, that lead to extensive production of sialidase, for example, in gas edema.371 In the oral cavity, plaque formation and dental caries may be influenced by desialylation of salivary glycoconjugates,399 and bacterial sialidases may play a role therein. This process may be retarded by secretion of the inhibitor Neu2en5Ac in saliva at concentrations which, in some cases, were found to be close to the K value for sialidases.34... 

Fig. 24. Molecular surface of group-1 (Nl) sialidase with bound Oseltamivir showing the 150-cavity.

NEW INFLUENZA VIRUS SIALIDASE INHIBITORS TARGETING THE 150-CAVITY... 

Modeling studies carried out by Mark von Itzstein s group [ 137] on the 150-loop open structures of group 1 sialidase Nl revealed the possibility to access the predominantly hydrophobic 150-cavity by an appropriate substitution at C3 of 11. As shown in Figure 17.18, an opportune substitution at C3 of 11 would be accommodated in the 150-cavity in the more open form of influenza virus sialidase of group 1 and could also potentially bind to the active site with minimal distortion of the normal binding mode of 11. 

FIGURE 17.17 Sialidase inhibitors designed to target the 150-cavity. 

X-ray crystallography studies with group 1 sialidase N8 revealed the ability of the C3-substituent of derivative 31 to occupy the area of the 150-cavity and maintain the 150-loop in an open form (Fig. 17.19a, b) [137]. However, when 11 was bound to the active site of N8, a closed conformation of the 150-loop was observed (Fig. 17.19c). 

Structure of the sialidase active site with sialic acid bound, showing the region of the pocket with space for fitting an extra group to the right of the molecule. The blue net is a van der Waals surface and indicates the accessible surface of the cavity. 

There are five general regions of the active site (depicted as S1-S5 in Figure 22.5) [106]. These binding regions, and the conserved interacting residues, are common to influenza A and B virus sialidases. An additional cavity adjacent to subsites 1 and 2 of the active site has been observed in more recent structures of some influenza A virus sialidases [66,107]. The accessibility of this... 

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