Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase
Open Access
- 16 November 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 1 (1), 113
- https://doi.org/10.1038/ncomms1114
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.Keywords
This publication has 33 references indexed in Scilit:
- The 2009 pandemic H1N1 neuraminidase N1 lacks the 150-cavity in its active siteNature Structural & Molecular Biology, 2010
- 2009 H1N1 InfluenzaMayo Clinic Proceedings, 2010
- Zanamivir-Resistant Influenza Viruses with a Novel Neuraminidase MutationJournal of Virology, 2009
- Characterizing Loop Dynamics and Ligand Recognition in Human- and Avian-Type Influenza Neuraminidases via Generalized Born Molecular Dynamics and End-Point Free Energy CalculationsJournal of the American Chemical Society, 2009
- Ensemble-Based Virtual Screening Reveals Potential Novel Antiviral Compounds for Avian Influenza NeuraminidaseJournal of Medicinal Chemistry, 2008
- Remarkable Loop Flexibility in Avian Influenza N1 and Its Implications for Antiviral Drug DesignJournal of the American Chemical Society, 2007
- Natural Variation Can Significantly Alter the Sensitivity of Influenza A (H5N1) Viruses to OseltamivirAntimicrobial Agents and Chemotherapy, 2006
- Coot: model-building tools for molecular graphicsActa Crystallographica Section D-Biological Crystallography, 2004
- SWISS‐MODEL and the Swiss‐Pdb Viewer: An environment for comparative protein modelingElectrophoresis, 1997
- The CCP4 suite: programs for protein crystallographyActa Crystallographica Section D-Biological Crystallography, 1994