Carbocycles Related to Oseltamivir as Influenza Virus Group-1-Specific Neuraminidase Inhibitors. Binding to N1 Enzymes in the Context of Virus-like Particles

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Title Carbocycles Related to Oseltamivir as Influenza Virus Group-1-Specific Neuraminidase Inhibitors. Binding to N1 Enzymes in the Context of Virus-like Particles
Author Mohan, Sankar; McAtamney, Sarah; Haselhorst, Thomas Erwin; von Itzstein, Mark; Pinto, Brian Mario
Journal Name Journal of Medicinal Chemistry
Year Published 2010
Place of publication United States
Publisher American Chemical Society
Abstract We report here the exploitation of the 150-cavity in the active sites of group-1 neuraminidases for the design of new triazole-containing carbocycles related to oseltamivir. Inhibition studies with virus-like particles (VLPs) containing the influenza virus neuraminidase-1 (N1) activity indicate that several candidates are inhibitors, with Ki values in the 10−5−10−8 M range. In contrast, a known candidate that preserves the free amino group and a new candidate containing a guanidine function are better inhibitors, with Ki values of 1.5 × 10−9 and 4.6 × 10−10 M, respectively. The most active inhibitor of the N1 enzyme in the triazole series was selective for the N1 class and showed significantly less inhibition (Ki = 2.6 μM vs 0.07 μM) of the free influenza virus neuraminidase-2 (N2). In addition, saturation transfer difference (STD) NMR spectroscopic studies with this compound and the VLPs show that the entire molecule forms contacts with residues in the active site. These data taken together support our proposed binding mode in which the active site and the adjoining 150-cavity are both occupied.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1021/jm100822f
Copyright Statement Self-archiving of the author-manuscript version is not yet supported by this journal. Please refer to the journal link for access to the definitive, published version or contact the authors for more information.
Volume 53
Issue Number 20
Page from 7377
Page to 7391
ISSN 0022-2623
Date Accessioned 2011-01-21
Date Available 2011-03-01T08:30:54Z
Language en_AU
Research Centre Institute for Glycomics
Faculty Faculty of Science, Environment, Engineering and Technology
Subject Medicinal and Biomolecular Chemistry
URI http://hdl.handle.net/10072/35815
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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