Structural analysis of a designed inhibitor complexed with the hemagglutinin-neuraminidase of Newcastle disease virus

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Title Structural analysis of a designed inhibitor complexed with the hemagglutinin-neuraminidase of Newcastle disease virus
Author Ryan, Charlotte; Zaitsev, Viateslav; Tindal, David James; Dyason, Jeffrey Clifford; Thomson, Robin Joy; Alymova, Irina; Porter, Allen; von Itzstein, Mark; Taylor, Garry
Journal Name Glycoconjugate Journal
Year Published 2006
Place of publication United States
Publisher Springer
Abstract Viruses of the Paramyxoviridae family are the leading cause of respiratory disease in children. The human parainfluenza viruses (hPIV) are members of the Paramyxovirinae subfamily, which also includes mumps virus, Newcastle disease virus (NDV), Sendai virus (SV) and simian type 5 virus (SV5). On the surface of these viruses is the glycoprotein hemagglutinin-neuraminidase (HN), which is responsible for cell attachment, promotion of fusion and release of progeny virions. This multifunctional nature of HN makes it an attractive target for the development of inhibitors as a treatment for childhood respiratory diseases. Here we report the crystal structure of NDV HN in complex with a derivative of 2-deoxy-2,3-dehydro-Nacetylneuraminic acid, Neu5Ac2en, that has a functional group designed to occupy a large conserved binding pocket around the active site. The purpose of this study was to examine the effect of a bulky hydrophobic group at the O4 position of Neu5Ac2en, given the hydrophobic nature of the binding pocket. This derivative, with a benzyl group added to the O4 position of Neu5Ac2en, has an IC50 of ∼10 μM in a neuraminidase assay against hPIV3 HN. The IC50 value of the parent compound, Neu5Ac2en, in the same assay is ∼25 μM. These results highlight the striking difference between the influenza neuraminidase and paramyxovirus HN active sites, and provide a platform for the development of improved HN inhibitors.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1007/s10719-006-5446-8
Volume 23
Page from 135
Page to 141
ISSN 0282-0080
Date Accessioned 2007-02-23
Date Available 2010-08-26T07:35:43Z
Language en_AU
Research Centre Institute for Glycomics
Faculty Institute for Glycomics
Subject PRE2009-Enzymes
URI http://hdl.handle.net/10072/13715
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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