权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Development of new influenza virus treatments based an the findings of triggering proteases for influenza virus entry into the cells and on the findings of protease-activating receptors

基于触发流感病毒进入细胞的蛋白酶的发现以及蛋白酶激活受体的发现，开发新的流感病毒治疗方法

基本信息

批准号：
13557014
负责人：
KIDO Hiroshi
金额：
$ 8.9万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

Influenza virus infection including pandemic avian influenza virus in 2003 is one of the mast common infectious pathogens in humans and causes considerable morbidity and mortality. Recently inhibitors of influenza virus neuraminidase have been developed as anti-influenza drugs, which inhibit virus release from the cells at the budding stage. On the other hand, we have developed the inhibitar of virus envelope protein processing protease, which inhibit virus entry into the cells. In the term of this research project, we found four different bast cellular influenza virus envelope glycoprotein processing proteases, such as mini-plasmin, ectopic anionic trypsin, TMPRSS7 and TC30, other than tryptase Clara. These proteases distributed different locations in the airway and revealed different susceptibility for the virus envelope glycoprotein of various subtypes. Among them, expression of ectopic anionic trypsin increased in the lungs alter virus infection and may play a role in progression of virus spread and pneumonia. Mini-plasmin levels also increased at the inflammatory loci in the lungs after virus infection and accumulated on the cerebral capillaries through blood f low in mice having an impaired mitochondrial β-oxidation. In addition, accumulated mini-plasnmin destructed blood-brain barrier, resulting in brain edema and multiplication of the influenza virus in the brain capillaries. These findings implicate that disorder of mitochondrial β-oxidation and accumulation of mini-plasmin in the brain capillaries are the principal pathogens of influenza associated encephalopathy and Rye s syndrome. Based on these results, inhibitors of these virus envelope glycoprotein processing proteases may be important candidates for novel anti-influenza drugs. we are trying to find inhibitors of these processing proteases as anti-influenza drugs

流感病毒感染包括2003年发生的禽流感病毒大流行，是人类最常见的传染病病原体之一，其发病率和死亡率相当高。近年来，流感病毒神经氨酸酶抑制剂被开发为抗流感药物，其抑制病毒在萌芽阶段从细胞中释放。另一方面，我们开发了病毒包膜蛋白加工蛋白酶抑制剂，抑制病毒进入细胞。在本研究项目中，我们发现了除类胰蛋白酶Clara外，还有四种不同的流感病毒韧皮细胞膜糖蛋白加工蛋白酶，如mini-plasmin、异位阴离子胰蛋白酶、TMPRSS 7和TC 30。这些蛋白酶分布在气道的不同部位，并揭示了不同亚型的病毒包膜糖蛋白的不同易感性。其中，异位阴离子胰蛋白酶的表达在病毒感染后在肺中增加，并且可能在病毒传播和肺炎的进展中起作用。病毒感染后，肺中炎症部位的微纤溶酶水平也增加，并通过线粒体β-氧化受损的小鼠的血流在脑毛细血管上积累。此外，微纤溶酶的蓄积破坏血脑屏障，导致脑水肿和流感病毒在脑毛细血管内的增殖。提示脑毛细血管线粒体β-氧化功能紊乱和微小纤溶酶的蓄积是流感相关脑病和Rye综合征的主要病因。基于这些结果，这些病毒包膜糖蛋白加工蛋白酶的抑制剂可能是新型抗流感药物的重要候选物。我们正试图找到这些蛋白酶的抑制剂作为抗流感药物