The Catalytic Mechanism of Human Parainfluenza Virus Type 3 Haemagglutinin-Neuraminidase Revealed
The Catalytic Mechanism of Human Parainfluenza Virus Type 3 Haemagglutinin-Neuraminidase Revealed
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DOI：
10.1002/anie.201412243
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发表时间：
2015-03-02
影响因子：
16.6
通讯作者：
von Itzstein, Mark
中科院分区：
文献类型：
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作者：
Dirr, Larissa;El-Deeb, Ibrahim M.;von Itzstein, Mark
人副流感病毒3型（hPIV-3）是儿童下呼吸道疾病的主要原因之一，迄今为止既没有批准的抗病毒药物也没有疫苗。了解人副流感病毒血凝素-神经氨酸酶（HN）蛋白的催化机制是设计针对该病毒的特异性抑制剂的关键。在此，我们使用（HNMR）-H-1光谱，X-射线晶体学，和病毒学分析研究HN酶活性的催化机制，并确定了保守的Tyr 530作为参与催化的关键氨基酸。一种新型的2，3-二氟唾液酸衍生物表现出较长的酶抑制作用，并与Tyr 530反应形成共价键。此外，该新型衍生物在病毒阻断试验中相对于其Neu 2 en类似物表现出增强的效力。这些结果为新一代针对hPIV-3 HN的强效抑制剂打开了大门。
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.