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

• DOI: 10.1038/ncomms1114
• Publication Date: 2010-11-16T11:47:47Z
• Authors: Santosh Rudrawar; Jeffrey C. Dyason; Marie-Anne Rameix...; Faith J. Rose; Philip S. Kerry; Rupert J. M. Russell; Sylvie van der Werf; Robin J. Thomson; Nadia Naffakh; Mark von Itzstein
• Keywords: Sialidase; Viral life cycle

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