Structural analysis of a designed inhibitor complexed with the hemagglutinin-neuraminidase of Newcastle disease virus.
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-N-acetylneuraminic 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 IC(50) of approximately 10 microM in a neuraminidase assay against hPIV3 HN. The IC(50) value of the parent compound, Neu5Ac2en, in the same assay is approximately 25 microM. 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.
Centre for Biomolecular Sciences, University of St Andrews, St Andrews, Fife, KY16 9ST, Scotland, UK.
Charlotte
C
Ryan
Viateslav
V
Zaitsev
David J
DJ
Tindal
Jeffrey C
JC
Dyason
Robin J
RJ
Thomson
Irina
I
Alymova
Allen
A
Portner
Mark
M
von Itzstein
Garry
G
Taylor
D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015707:HN Protein / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D009522:Newcastle disease virus; D011487:Protein Conformation
D004791:Enzyme Inhibitors; D015707:HN Protein; C036137:2-deoxy-2,3-dehydro-N-acetylneuraminic acid; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid