Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase
MetadataShow full item record
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.
Rudrawar , S , Dyason , J C , Rameix-Welti , M A , Rose , F J , Kerry , P S , Russell , R J M , van der Werf , S , Thomson , R J , Naffakh , N & von Itzstein , M 2010 , ' Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase ' Nature Communications , vol 1 , 113 . , 10.1038/ncomms1114
© 2010 Macmillan Publishers Limited. This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
This work was supported by the Medical Research Council and the Scottish Funding Council.
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.