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Issue 43, 2012
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Synthesis and evaluation of novel 3-C-alkylated-Neu5Ac2en derivatives as probes of influenza virus sialidase 150-loop flexibility

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Abstract

Novel 3-C-alkylated-Neu5Ac2en derivatives have been designed to target the expanded active site cavity of influenza virus sialidases with an open 150-loop, currently seen in X-ray crystal structures of influenza A virus group-1 (N1, N4, N5, N8), but not group-2 (N2, N9), sialidases. The compounds show selectivity for inhibition of H5N1 and pdm09 H1N1 sialidases over an N2 sialidase, providing evidence of the relative 150-loop flexibility of these sialidases. In a complex with N8 sialidase, the C3 substituent of 3-phenylally-Neu5Ac2en occupies the 150-cavity while the central ring and the remaining substituents bind the active site as seen for the unsubstituted template. This new class of inhibitors, which can ‘trap’ the open 150-loop form of the sialidase, should prove useful as probes of 150-loop flexibility.

Graphical abstract: Synthesis and evaluation of novel 3-C-alkylated-Neu5Ac2en derivatives as probes of influenza virus sialidase 150-loop flexibility

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Publication details

The article was received on 26 Mar 2012, accepted on 24 Aug 2012 and first published on 28 Aug 2012


Article type: Paper
DOI: 10.1039/C2OB25627D
Citation: Org. Biomol. Chem., 2012,10, 8628-8639
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    Synthesis and evaluation of novel 3-C-alkylated-Neu5Ac2en derivatives as probes of influenza virus sialidase 150-loop flexibility

    S. Rudrawar, P. S. Kerry, M. Rameix-Welti, A. Maggioni, J. C. Dyason, F. J. Rose, S. van der Werf, R. J. Thomson, N. Naffakh, R. J. M. Russell and M. von Itzstein, Org. Biomol. Chem., 2012, 10, 8628
    DOI: 10.1039/C2OB25627D

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