Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase
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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 . DOI: 10.1038/ncomms1114
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This work was supported by the Medical Research Council and the Scottish Funding Council.
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