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

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.

• Authors: Patrice Guillon, Larissa Dirr, Ibrahim M El-Deeb, Moritz Winger, Benjamin Bailly, Thomas Haselhorst, Jeffrey C Dyason, Mark von Itzstein
• Journal: Nature communications (Nat Commun) Vol. 5 Pg. 5268 (Oct 20 2014) ISSN: 2041-1723 [Electronic] England
• PMID: 25327774 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Enzyme Inhibitors
• Hemagglutinins, Viral
• Neuraminic Acids
• Recombinant Proteins
• Solvents
• Neuraminidase

Topics

• Antiviral Agents (chemistry)
• Catalytic Domain
• Cell Line, Tumor
• Computer Simulation
• Crystallography, X-Ray
• Drug Design
• Enzyme Inhibitors (chemistry)
• Enzyme-Linked Immunosorbent Assay
• Epitope Mapping
• Hemagglutinins, Viral (chemistry)
• Humans
• Inhibitory Concentration 50
• Magnetic Resonance Spectroscopy
• Molecular Conformation
• Molecular Dynamics Simulation
• Neuraminic Acids (chemistry)
• Neuraminidase (antagonists & inhibitors)
• Parainfluenza Virus 3, Human
• Recombinant Proteins (chemistry)
• Solvents (chemistry)
• Surface Properties