A dual drug regimen synergistically blocks human parainfluenza virus infection.

Benjamin Bailly (1, 2) , Larissa Dirr (2) , Ibrahim M El-Deeb (2) , Ralf Altmeyer (1) , Patrice Guillon (2) , Mark von Itzstein (2)

1 IPS-CAS - Institut Pasteur de Shanghai, Académie des Sciences de Chine - Chinese Academy of Sciences
2 Institute for Glycomics

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.

Keywords: Molecular docking; Enzyme kinetics; STD-NMR; Parainfluenza virus; Drug discovery; Antivirals; Drug combinations

Domains: Virology

Benjamin Bailly, Larissa Dirr, Ibrahim M El-Deeb, Ralf Altmeyer, Patrice Guillon, et al.. A dual drug regimen synergistically blocks human parainfluenza virus infection.. Scientific Reports, 2016, 6 (24138), pp.24138. ⟨10.1038/srep24138⟩. ⟨pasteur-01302307⟩