Novel Compounds Targeting the Mitochondrial Protein VDAC1 Inhibit Apoptosis and Protect against Mitochondrial Dysfunction
Novel Compounds Targeting the Mitochondrial Protein VDAC1 Inhibit Apoptosis and Protect against Mitochondrial Dysfunction
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DOI：
10.1074/jbc.m116.744284
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发表时间：
2016-11-25
影响因子：
4.8
通讯作者：
Shoshan-Barmatz, Varda
中科院分区：
文献类型：
--
作者：
Ben-Hail, Danya;Begas-Shvartz, Racheli;Shoshan-Barmatz, Varda
细胞凋亡被认为在一些病理过程中起关键作用，例如神经退行性疾病（即帕金森病和阿尔茨海默病）和各种心血管疾病。尽管凋亡机制已经被很好地定义，但仍然没有实质性的治疗策略来阻止甚至减缓这一过程。因此，对于能够阻断或减缓神经退行性疾病和心血管疾病中的细胞凋亡的治疗剂存在未满足的需求。线粒体外膜蛋白电压依赖性阴离子通道1（VDAC 1）是多种细胞存活和死亡信号（包括凋亡）的汇聚点。最近，我们证明VDAC 1寡聚化参与了细胞因子介导的凋亡。因此，VDAC 1寡聚化代表了设计用于调节细胞凋亡的药剂的主要靶标。在此，采用高通量化合物筛选和药物化学来开发与VDAC 1直接相互作用并防止VDAC 1寡聚化的化合物，同时抑制通过各种手段和在各种细胞系中诱导的细胞凋亡。这些化合物可防止糖尿病相关的线粒体功能障碍，恢复消散的线粒体膜电位，从而恢复细胞能量和代谢，减少反应性氧化物质的产生，并防止与线粒体结合的己糖激酶脱离和细胞内Ca 2+水平的破坏。因此，本研究描述了具有明确作用机制的新型候选药物，包括抑制VDAC 1寡聚化、细胞凋亡和线粒体功能障碍。化合物VBIT-3和VBIT-4提供了治疗与增强的细胞凋亡相关的不同疾病的治疗策略，并指出VDAC 1是治疗干预的有希望的靶点。
Apoptosis is thought to play a critical role in several pathological processes, such as neurodegenerative diseases (i.e. Parkinson's and Alzheimer's diseases) and various cardiovascular diseases. Despite the fact that apoptotic mechanisms are well defined, there is still no substantial therapeutic strategy to stop or even slow this process. Thus, there is an unmet need for therapeutic agents that are able to block or slow apoptosis in neurodegenerative and cardiovascular diseases. The outer mitochondrial membrane protein voltage-dependent anion channel 1 (VDAC1) is a convergence point for a variety of cell survival and death signals, including apoptosis. Recently, we demonstrated that VDAC1 oligomerization is involved in mitochondrion-mediated apoptosis. Thus, VDAC1 oligomerization represents a prime target for agents designed to modulate apoptosis. Here, high-throughput compound screening and medicinal chemistry were employed to develop compounds that directly interact with VDAC1 and prevent VDAC1 oligomerization, concomitant with an inhibition of apoptosis as induced by various means and in various cell lines. The compounds protected against apoptosis-associated mitochondrial dysfunction, restoring dissipated mitochondrial membrane potential, and thus cell energy and metabolism, decreasing reactive oxidative species production, and preventing detachment of hexokinase bound to mitochondria and disruption of intracellular Ca2+ levels. Thus, this study describes novel drug candidates with a defined mechanism of action that involves inhibition of VDAC1 oligomerization, apoptosis, and mitochondrial dysfunction. The compounds VBIT-3 and VBIT-4 offer a therapeutic strategy for treating different diseases associated with enhanced apoptosis and point to VDAC1 as a promising target for therapeutic intervention.