title: A dual drug regimen synergistically blocks human parainfluenza virus infection.
abstract: Human parainfluenza type-3 virus (hPIV-3) is one of the principal aetiological agents of acute respiratory illness in infants worldwide and also shows high disease severity in the elderly and immunocompromised, but neither therapies nor vaccines are available to treat or prevent infection, respectively. Using a multidisciplinary approach we report herein that the approved drug suramin acts as a non-competitive in vitro inhibitor of the hPIV-3 haemagglutinin-neuraminidase (HN). Furthermore, the drug inhibits viral replication in mammalian epithelial cells with an IC50 of 30 μM, when applied post-adsorption. Significantly, we show in cell-based drug-combination studies using virus infection blockade assays, that suramin acts synergistically with the anti-influenza virus drug zanamivir. Our data suggests that lower concentrations of both drugs can be used to yield high levels of inhibition. Finally, using NMR spectroscopy and in silico docking simulations we confirmed that suramin binds HN simultaneously with zanamivir. This binding event occurs most likely in the vicinity of the protein primary binding site, resulting in an enhancement of the inhibitory potential of the N-acetylneuraminic acid-based inhibitor. This study offers a potentially exciting avenue for the treatment of parainfluenza infection by a combinatorial repurposing approach of well-established approved drugs.
authors.affiliation: Institute for Glycomics, Gold Coast Campus, Griffith University, Gold Coast, 4222, Australia.|Unit of anti-infective research, Institut Pasteur of Shanghai - Chinese Academy of Sciences, Shanghai, 200031, P.R. China.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bailly
authors.affiliation: Institute for Glycomics, Gold Coast Campus, Griffith University, Gold Coast, 4222, Australia.
authors.forename: Larissa
authors.initials: L
authors.lastname: Dirr
authors.affiliation: Institute for Glycomics, Gold Coast Campus, Griffith University, Gold Coast, 4222, Australia.
authors.forename: Ibrahim M
authors.initials: IM
authors.lastname: El-Deeb
authors.affiliation: Unit of anti-infective research, Institut Pasteur of Shanghai - Chinese Academy of Sciences, Shanghai, 200031, P.R. China.|Shandong University-Helmholtz Institute of Biotechnology, Qingdao, 266101, P.R. China.
authors.forename: Ralf
authors.initials: R
authors.lastname: Altmeyer
authors.affiliation: Institute for Glycomics, Gold Coast Campus, Griffith University, Gold Coast, 4222, Australia.
authors.forename: Patrice
authors.initials: P
authors.lastname: Guillon
authors.affiliation: Institute for Glycomics, Gold Coast Campus, Griffith University, Gold Coast, 4222, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: von Itzstein
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects* / Q000821:virology; D015707:HN Protein / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000187:drug effects; D007668:Kidney / Q000166:cytology; D007700:Kinetics; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D010224:Parainfluenza Virus 3, Human / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D013498:Suramin / Q000378:metabolism / Q000494:pharmacology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D053243:Zanamivir / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D015707:HN Protein; D014764:Viral Proteins; D013498:Suramin; D053243:Zanamivir