The Catalytic Mechanism of Human Parainfluenza Virus Type 3 Haemagglutinin-Neuraminidase Revealed

被引：29

作者：

Dirr, Larissa ^{[1
]}

El-Deeb, Ibrahim M. ^{[1
]}

Guillon, Patrice ^{[1
]}

Carroux, Cindy J. ^{[1
]}

Chavas, Leonard M. G. ^{[2
]}

von Itzstein, Mark ^{[1
]}

机构：

[1] Griffith Univ, Inst Glyc, Southport, Qld 4222, Australia

[2] DESY, Ctr Free Electron Laser Sci, D-22607 Hamburg, Germany

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2015年 / 54卷 / 10期

基金：

澳大利亚研究理事会; 英国医学研究理事会;

关键词：

haemagglutinin-neuraminidase; inhibitors; parainfluenza virus; sialic acid; sialidase mechanism; BIOLOGICAL EVALUATION; ACID-DERIVATIVES; C-4; POSITION; IN-VITRO; BCX; 2798; INHIBITORS; EFFICACY; TARGET;

D O I：

10.1002/anie.201412243

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Human parainfluenza virus type3 (hPIV-3) is one of the leading causes for lower respiratory tract disease in children, with neither an approved antiviral drug nor vaccine available to date. Understanding the catalytic mechanism of human parainfluenza virus haemagglutinin-neuraminidase (HN) protein is key to the design of specific inhibitors against this virus. Herein, we used (HNMR)-H-1 spectroscopy, X-ray crystallography, and virological assays to study the catalytic mechanism of the HN enzyme activity and have identified the conserved Tyr530 as a key amino acid involved in catalysis. A novel 2,3-difluorosialic acid derivative showed prolonged enzyme inhibition and was found to react and form a covalent bond with Tyr530. Furthermore, the novel derivative exhibited enhanced potency in virus blockade assays relative to its Neu2en analogue. These outcomes open the door for a new generation of potent inhibitors against hPIV-3 HN.

引用

页码：2936 / 2940

页数：5

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