Optimization of Furin Inhibitors To Protect against the Activation of Influenza Hemagglutinin H5 and Shiga Toxin
Optimization of Furin Inhibitors To Protect against the Activation of Influenza Hemagglutinin H5 and Shiga Toxin
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DOI：
10.1021/jm400633d
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发表时间：
2014-01-09
影响因子：
7.3
通讯作者：
Day, Robert
中科院分区：
文献类型：
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作者：
Gagnon, Hugo;Beauchemin, Sophie;Day, Robert
原蛋白转化酶（PCs）在病毒或细菌蛋白前体的加工和进入过程中起着至关重要的作用，并赋予具有PC激活位点的病原体更高的传染性，从而导致症状的严重程度和致死率增加。在此之前，我们开发了一种纳米摩尔的PC肽抑制剂来阻止感染因子的PC激活。在此，我们描述了一种拟肽方法，该方法增加了该抑制剂在体内使用的稳定性，以防止全身感染和细胞损伤，例如由H5N1流感和志贺毒素引起的感染。在基于细胞的实验中，在肽的两端添加aza β(3)-氨基酸成功地阻止了流感血凝素5的融合原性和志贺毒素的Vero毒性。利用shrna诱导的稳定蛋白转化酶敲低的细胞模型结果表明，只有furin是HAS裂解所需的主要蛋白转化酶。
Proprotein convertases (PCs) are crucial in the processing and entry of viral or bacterial protein precursors and confer increased infectivity of pathogens bearing a PC activation site, which results in increased symptom severity and lethality. Previously, we developed a nanomolar peptide inhibitor of PCs to prevent PC activation of infectious agents. Herein, we describe a peptidomimetic approach that increases the stability of this inhibitor for use in vivo to prevent systemic infections and cellular damage, such as that caused by influenza H5N1 and Shiga toxin. The addition of aza beta(3)-amino acids to both termini of the peptide successfully prevented influenza hemagglutinin 5 fusogenicity and Shiga toxin Vero toxicity in cell-based assays. The results from a cell-based model using stable shRNA-induced proprotein convertase knockdown indicate that only furin is the major proprotein convertase required for HAS cleavage.