Mammalian sialidases

Compound 34 (BCZ-1812, RWJ-270201, peramivir) showed selective inhibition of influenza virus sialidases over bacterial and mammalian sialidases (Babu et al. 2000 Bantia et al. 2001 Sidwell and Smee 2002). Successful inhibition of influenza virus infectivity in vitro (Smee et al. 2001) and upon oral administration in vivo [mice (Bantia et al. 2001) and ferrets, reviewed in Sidwell and Smee 2002] led to human clinical trials of orally administered peramivir (Barroso et al. 2005). While orally administrated peramivir successfully completed animal studies and Phase I and Phase II clinical trials, in which the compound was showing neither major side effects nor toxicity (Sidwell and Smee 2002), preliminary results of the Phase III trials (June 2002) demonstrated no statistically significant difference in the primary efficacy endpoint, possibly due to low bioavailability (Barroso et al. 2005). 

The internal, sialyl residue of GM, is not completely resistant to some sialidases, so long as the oligosaccharide chain is bound to the ceramide part of GM, it is slowly cleaved by C. perfringens sialidase in the presence of bile salts.77 57 3511 Surprisingly, it is a relatively good substrate for the A. ureafaciens sialidase.360 Rapid hydrolysis of GM, sialic acid has also been observed with Sendai virus sialidase, in contrast to the enzymes from NDV or influenza viruses.361 Susceptibility towards mammalian sialidases has also been reported.362 However, it... 

Since the tertiary structure of bacterial sialidases is similar to that found in viral sialidases (e.g. refs. [756,792-794], for a review see ref. [246]) and residues of the Asp-box have also been found, viral and bacterial sialidases can be considered to belong to one enzyme family. The few mammalian sialidases sequenced so far, i.e. from rat muscle [774] or hamster ovary cells [775], as well as trypanosomal sialidases (see in section 9.2.3), also show many structural features in common with viral and bacterial sialidases and are correspondingly members of this family. A DNA sequence of human origin showing features similar to microbial sialidase genes is also known [795]. However,... 

Another important feature, especially from the viewpoint of rational drug design, zanamivir (12) shows a remarkable degree of selectivity towards influenza virus sialidase. In experiments aimed at determining the specificity of (12) towards influenza sialidase it was shown that zanamivir [as well as the 4-amino derivative (11)] did not show any increase in inhibition of other viral, bacterial, or mammalian sialidases when compared with Neu5Ac2en (6) [73, 87]. The results of some of these studies are presented in the clinical summary section of this article. This selectivity has been explained on the basis of the active site architecture of the different sialidases, in that it is only influenza virus sialidase which can accomodate the relatively bulky and basic C-4 substituent in its catalytic site [73]. 

The fourth member of the mammalian sialidase family, NEU4, has been identified by searching sequence databases for entries showing homologies to human cytosolic sialidase One peeuliar feature of this enzyme is the presence of a long... 

L. Anastasia, J. Holguera, A. Bianchi, F. D Avila, N. Papini, C. Tringali, E. Monti, E. Villar, B. Venerando, I. Munoz-Barroso, and G. Tettamanti, Overexpression of mammalian sialidase NEU3 reduces Newcastle disease virus entry and propagation in COS7 cells, Biochim. Biophys. Acta, 1780 (2008) 504-512. 

Neu5Ac2en 14 was an interesting inhibitor template with micromolar activity, but was not selective, inhibiting microbial and mammalian sialidases alike. 

Miyagi, T. and Yamaguchi, K. (2012) Mammalian sialidases physiological and pathological roles in cellular functions. Glycobiology, 22, 880-896. 

Recent studies have implicated the existence of a hydrophobic centre distinct from the catalytic centre in V. cholerae (Keilich et al. 1979) and C. perfringens (Corfield et al. 1980) sialidases. The detection of multiple sialidase activities in bacterial, protozoan and mammalian sialidase preparations using immobilized N-(4-nitrophenyl)-oxamic acid columns has supported these observations (Brossmer et al. 1977 b, Crampen et al 1979, Ziegler et al 1980). Those sialidases showing affinity for the immobilized ligand also showed low activity with synthetic... 

Table 4. The influence of inhibitors on viral, bacterial and mammalian sialidases The strength of inhibition is indicated as weak (+) to very strong (-h + -H) or no inhibition (—). High (H) and low (L) molecular weight inhibitors are indicated and inhibition as competitive (C) or non-competitive (NC). ND, not determined... 

A.P. Corfield, R.W. Veh, M. Wember, J.C. Michalski and R. Schauer, The release of N-acetyl and N-glycolloyl-neuraminic acid from soluble complex carbohydrates and erythrocytes by bacterial, viral and mammalian sialidases. Biochem. J., 1981, 197, 293-299. 

---