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Development of anti-and pro-apoptotic drugs via regulation of VDAC, a mitochondrial outermembrane protein

通过调节 VDAC（一种线粒体外膜蛋白）开发抗凋亡和促凋亡药物

基本信息

批准号：
14370058
负责人：
SHIMIZU Shigeomi
金额：
$ 8.26万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370058/
关键词：
aptosis mitochondria VDAC Bcl-2 Tat-BH4 BH4

项目摘要

Voltage-dependent anion channel (VDAC) is a channel protein existed on mitochondrial outer membrane. VDAC plays a crucial role for cell living as well as cell death, via regulating mitochondrial membrane permeability. Therefore, in order to develop the anti-and pro-apoptotic drugs, I planned two studies ; (1)Identification of VDAC-regulating drugs, and (2)Development of drugs that inhibit VDAC-hexokinase interaction, which is crucial for cancer cell viability through regulation of glycolysis.(1)Identification of VDAC-regulating drugs-(A)Previously, I found that anti-apoptotic protein Bcl-2/Bcl-xL regulated VDAC through direct interaction. I searched the binding site and found that N-terminal 20 amino acids (called BH4 region) were crucial. To produce cell-permeable form, 9 amino acids derived from HIV-Tat protein were fused. This Tat-BH4 peptide closed VDAC channel in isolated mitochondria, and prevented various forms of apoptosis in cultured cells. Furthermore, when this peptides were administrated into mice, radiation-induced colitis, ischemic heart disease, and fulminant hepatitis were dramatically improved. (B)To identify other VDAC-regulating agents, I screened the various antibiotics and small molecules using isolated mitochondria. From antibiotics library, I found several molecules which cancelled anti-apoptotic Bcl-2 function via regulating VDAC channel, from small molecules screening, I found anti-apoptotic reagent. Now, I tested the effect of these molecules in vivo.(2)Development of drugs that inhibit VDAC-hexokinase interaction-Although I tried several screening to identify the drugs that inhibit VDAC-hexokinase interaction. But, I could not identified yet.

电压依赖性阴离子通道（VDAC）是存在于线粒体外膜上的一种通道蛋白。VDAC通过调节线粒体膜通透性，对细胞存活和细胞死亡起着至关重要的作用。因此，为了开发抗凋亡和促凋亡药物，我计划了两项研究：（1）鉴定VDAC调节药物，和（2）开发抑制VDAC-己糖激酶相互作用的药物，这对通过调节糖酵解的癌细胞活力至关重要。（1）VDAC调节药物的鉴定-（A）以前，我发现抗凋亡蛋白Bcl-2/Bcl-xL通过直接相互作用调节VDAC。我搜索了结合位点，发现N端20个氨基酸（称为BH 4区）是至关重要的。为了产生细胞可渗透的形式，融合来自HIV-Tat蛋白的9个氨基酸。这种Tat-BH 4肽在分离的线粒体中关闭VDAC通道，并防止培养细胞中各种形式的凋亡。此外，当将这种肽给予小鼠时，辐射诱导的结肠炎、缺血性心脏病和暴发性肝炎得到显著改善。(B)To为了鉴定其他VDAC调节剂，我使用分离的线粒体筛选了各种抗生素和小分子。从抗生素库中发现了几种通过调节VDAC通道而取消Bcl-2抗凋亡功能的分子，从小分子筛选中发现了抗凋亡试剂。现在，我测试了这些分子在体内的作用。（2）抑制VDAC-己糖激酶相互作用的药物开发-尽管我尝试了几次筛选来鉴定抑制VDAC-己糖激酶相互作用的药物。但是，我还不能确定。