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Targeting Human Parainfluenza Virus Type-1 Haemagglutinin-Neuraminidase with Mechanism-Based Inhibitors

Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Viruses 2019, 11(5), 417; https://doi.org/10.3390/v11050417
Received: 1 March 2019 / Revised: 23 April 2019 / Accepted: 29 April 2019 / Published: 5 May 2019
(This article belongs to the Special Issue The Glycobiology of Viral Infections)
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Abstract

Human parainfluenza virus (hPIV) infections are a major cause of respiratory tract illnesses in children, with currently no available vaccine or drug treatment. The surface glycoprotein haemagglutinin-neuraminidase (HN) of hPIV has a central role in the viral life cycle, including neuraminic acid-recognising receptor binding activity (early stage) and receptor-destroying activity (late stage), which makes it an ideal target for antiviral drug disovery. In this study, we showed that targeting the catalytic mechanism of hPIV-1 HN by a 2α,3β-difluoro derivative of the known hPIV-1 inhibitor, BCX 2798, produced more potent inhibition of the neuraminidase function which is reflected by a stronger inhibition of viral replication. The difluorosialic acid-based inhibitor efficiently blocked the neuraminidase activity of HN for a prolonged period of time relative to its unsaturated neuraminic acid (Neu2en) analogue, BCX 2798 and produced a more efficient inhibition of the HN neuraminidase activity as well as in vitro viral replication. This prolonged inhibition of the hPIV-1 HN protein suggests covalent binding of the inhibitor to a key catalytic amino acid, making this compound a new lead for a novel class of more potent hPIV-1 mechanism-based inhibitors. View Full-Text
Keywords: parainfluenza; haemagglutinin; neuraminidase; difluorosialic acid; glycohydrolase; sialidase; inhibitor parainfluenza; haemagglutinin; neuraminidase; difluorosialic acid; glycohydrolase; sialidase; inhibitor
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Eveno, T.; Dirr, L.; El-Deeb, I.M.; Guillon, P.; von Itzstein, M. Targeting Human Parainfluenza Virus Type-1 Haemagglutinin-Neuraminidase with Mechanism-Based Inhibitors. Viruses 2019, 11, 417.

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