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

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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.