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

Santosh Rudrawar (1) , Jeffrey C Dyason (1) , Marie-Anne Rameix-Welti (2) , Faith J Rose (1) , Philip S Kerry (3) , Rupert J M Russell (3) , Sylvie van Der Werf (2) , Robin J Thomson (1) , Nadia Naffakh (2) , Mark von Itzstein (1)

1 Institute for Glycomics
2 Génétique Moléculaire des Virus Respiratoires
3 Interdisciplinary Centre for Human and Avian Influenza Research

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.

Domains: Life Sciences [q-bio]; Microbiology and Parasitology

Santosh Rudrawar, Jeffrey C Dyason, Marie-Anne Rameix-Welti, Faith J Rose, Philip S Kerry, et al.. Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase.. Nature Communications, 2010, 1 (8), pp.113. ⟨10.1038/ncomms1114⟩. ⟨pasteur-00546706⟩