These in silico studies have been supported by evidence of a partially open 150-loop in a complex of N2 and Oseltamivir 17. More specifically, molecular dynamics studies have indicated that all NAs may retain the propensity for both “open” and “closed” states, maintaining an equilibrium that varies between strains 8, 15, 16. However, recently several studies have indicated that movement of the 150-loop may not be restricted to group-1 NA. As a consequence, inhibition of NA activity by this compound was described as group-specific, with substantially greater inhibition of group-1 than group-2 NAs. 1), an inhibitor based on the transition state analogue Neu5Ac2en, was demonstrated to insert into the 150-cavity and prevent closure of the 150-loop 12. The discovery of the 150-cavity has lead to the development of several inhibitors designed to exploit contacts in this region and increase specificity 11, 12, 13, 14. In the subsequent complex the 150-loop occupies a position similar to that observed in structures of group-2 NAs. While this cavity was present in structures of the apo form of most group-1 NAs (some controversy surrounds the structure of the NA from a H1N1 2009 pandemic strain 7, 8, 9, 10), it appears to be closed by movement of the 150-loop in response to ligand binding 4. Specifically, in the active sites of group 1 NAs a loop, consisting of residues 147–152 (the 150-loop), adopts a conformation leading to the opening of a pocket to the side of the active site (also known as the 150 cavity). However, more recently the elucidation of several structures of group 1 NAs has highlighted key group-specific differences in the shape of the NA active site 4. Early structures of the catalytic head domain from group 2 subtypes N9 and N2 were the basis of drug development programmes leading to the production of Oseltamivir and Zanamivir. In addition, recombinant N10 protein showed no or extremely low sialidase activity in assay using 2′-(4-methylumbelliferyl)-α-D- N-acetylneuraminic acid (4-MU-NANA) as a substrate or with natural substrates in a glycan microarray assay 5, 6. The N10 subtype is considered to be a “NA-like” protein rather than a true NA as it was found to have only 20–27% sequence identity with other NA subtypes. There are ten known subtypes of NA (N1-10) 3, which have been classified by phylogenetic analyses into two distinct groups: group 1 (N1, N4, N5 and N8) and group 2 (N2, N3, N6, N7 and N9) 4. Inhibition of this process prevents the release of nascent virions from the surface of the cell, reducing the spread of the infection. The Influenza neuraminidase (NA) surface glycoprotein is responsible for the cleavage of sialic acid residues from the surface of the infected cell 2.
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