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

S Rudrawar, JC Dyason, MA Rameix-Welti, FJ Rose, Philip Stephen Kerry, Rupert James Martin Russell, S van der Werf, RJ Thomson, N Naffakh, M von Itzstein

Research output: Contribution to journalArticlepeer-review

99 Citations (Scopus)
3 Downloads (Pure)

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.
Original languageEnglish
Article number113
JournalNature Communications
Volume1
DOIs
Publication statusPublished - 16 Nov 2010

Fingerprint

Dive into the research topics of 'Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase'. Together they form a unique fingerprint.

Cite this