title: 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.affiliation: Institute for Glycomics, Gold Coast Campus, Griffith University, Gold Coast, Queensland 4222, Australia.
authors.forename: Patrice
authors.initials: P
authors.lastname: Guillon
authors.affiliation: Institute for Glycomics, Gold Coast Campus, Griffith University, Gold Coast, Queensland 4222, Australia.
authors.forename: Larissa
authors.initials: L
authors.lastname: Dirr
authors.affiliation: Institute for Glycomics, Gold Coast Campus, Griffith University, Gold Coast, Queensland 4222, Australia.
authors.forename: Ibrahim M
authors.initials: IM
authors.lastname: El-Deeb
authors.affiliation: Institute for Glycomics, Gold Coast Campus, Griffith University, Gold Coast, Queensland 4222, Australia.
authors.forename: Moritz
authors.initials: M
authors.lastname: Winger
authors.affiliation: Institute for Glycomics, Gold Coast Campus, Griffith University, Gold Coast, Queensland 4222, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bailly
authors.affiliation: Institute for Glycomics, Gold Coast Campus, Griffith University, Gold Coast, Queensland 4222, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haselhorst
authors.affiliation: Institute for Glycomics, Gold Coast Campus, Griffith University, Gold Coast, Queensland 4222, Australia.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Dyason
authors.affiliation: Institute for Glycomics, Gold Coast Campus, Griffith University, Gold Coast, Queensland 4222, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: von Itzstein
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D006389:Hemagglutinins, Viral / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009438:Neuraminic Acids / Q000737:chemistry; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D010224:Parainfluenza Virus 3, Human; D011994:Recombinant Proteins / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D013499:Surface Properties
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006389:Hemagglutinins, Viral; D009438:Neuraminic Acids; D011994:Recombinant Proteins; D012997:Solvents; D009439:Neuraminidase