Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase

This work was supported by the Medical Research Council and the Scottish Funding Council.Influenza virus sialidase has an essential role in the virus’ life cycle. Two distinct groups of influenza A virus sialidases have been established, that differ in the flexibility of the ‘150-loop’, providing a more open active site in the apo form of the group-1 compared to group-2 enzymes. In this study we show, through a multidisciplinary approach, that novel sialic acid-based derivatives can exploit this structural difference and selectively inhibit the activity of group-1 sialidases. We also demonstrate that group-1 sialidases from drug-resistant mutant influenza viruses are sensitive to these designed compounds. Moreover, we have determined, by protein X-ray crystallography, that these inhibitors lock open the group-1 sialidase flexible 150-loop, in agreement with our molecular modelling prediction. This is the first direct proof that compounds may be developed to selectively target the pandemic A/H1N1, avian A/H5N1 and other group-1 sialidase-containing viruses, based on an open 150-loop conformation of the enzyme.Publisher PDFPeer reviewe

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-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 占in a neuraminidase assay against hPIV3 HN. The IC50 value of the parent compound, Neu5Ac2en, in the same assay is ~25 卮 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.No Full Tex

A secondary sialic acid binding site on influenza virus neuraminidase: fact or fiction?

One flu over the cuckoo's nest: The biological significance of a secondary sialic acid binding site on influenza virus neuraminidase remains elusive. On blocking the active site influenza-virus-containing virus-like particles with oseltamivir carboxylate, binding to α(2,3)-sialyllactose is still detected. Thus the sialyllactose must bind at a secondary sialic acid binding site (see structures: docking study of α(2,3)-sialyllactose in the secondary binding site of avian flu neuraminidase). Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.link_to_subscribed_fulltex