Structure-guided discovery of potent and dual-acting human parainfluenza virus haemagglutinin–neuraminidase inhibitors

Patrice Guillon, Larissa Dirr, Ibrahim M. El-Deeb, Moritz Winger, Benjamin Bailly, Thomas Haselhorst, Jeffrey C. Dyason and Mark von Itzstein ()
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Patrice Guillon: Institute for Glycomics, Gold Coast Campus, Griffith University
Larissa Dirr: Institute for Glycomics, Gold Coast Campus, Griffith University
Ibrahim M. El-Deeb: Institute for Glycomics, Gold Coast Campus, Griffith University
Moritz Winger: Institute for Glycomics, Gold Coast Campus, Griffith University
Benjamin Bailly: Institute for Glycomics, Gold Coast Campus, Griffith University
Thomas Haselhorst: Institute for Glycomics, Gold Coast Campus, Griffith University
Jeffrey C. Dyason: Institute for Glycomics, Gold Coast Campus, Griffith University
Mark von Itzstein: Institute for Glycomics, Gold Coast Campus, Griffith University

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract Human parainfluenza viruses (hPIVs) cause upper and lower respiratory tract disease in children that results in a significant number of hospitalizations and impacts health systems worldwide. To date, neither antiviral drugs nor vaccines are approved for clinical use against parainfluenza virus, which reinforces the urgent need for new therapeutic discovery strategies. Here we use a multidisciplinary approach to develop potent inhibitors that target a structural feature within the hPIV type 3 haemagglutinin–neuraminidase (hPIV-3 HN). These dual-acting designer inhibitors represent the most potent designer compounds and efficiently block both hPIV cell entry and virion progeny release. We also define the binding mode of these inhibitors in the presence of whole-inactivated hPIV and recombinantly expressed hPIV-3 HN by Saturation Transfer Difference NMR spectroscopy. Collectively, our study provides an antiviral preclinical candidate and a new direction towards the discovery of potential anti-parainfluenza drugs.

Date: 2014
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DOI: 10.1038/ncomms6268

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