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

Viruses

卷:11

Mark von Itzstein¹  Larissa Dirr¹  IbrahimM. El-Deeb¹  Tanguy Eveno¹  Patrice Guillon¹ 

[1] Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia;

关键词: parainfluenza;    haemagglutinin;    neuraminidase;    difluorosialic acid;    glycohydrolase;    sialidase;    inhibitor;   

DOI  :  10.3390/v11050417

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown