title: Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase.
abstract: 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.
authors.affiliation: Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland 4222, Australia.
authors.forename: Santosh
authors.initials: S
authors.lastname: Rudrawar
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Dyason
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Rameix-Welti
authors.forename: Faith J
authors.initials: FJ
authors.lastname: Rose
authors.forename: Philip S
authors.initials: PS
authors.lastname: Kerry
authors.forename: Rupert J M
authors.initials: RJ
authors.lastname: Russell
authors.forename: Sylvie
authors.initials: S
authors.lastname: van der Werf
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Thomson
authors.forename: Nadia
authors.initials: N
authors.lastname: Naffakh
authors.forename: Mark
authors.initials: M
authors.lastname: von Itzstein