VBIT-4 is an inhibitor of voltage-dependent anion channel 1 (VDAC1) oligomerization, with a Kd value of 3μM for purified VDAC1 [1]. VBIT-4 induces depolarization of organelles fueled by substrates of complex I of the respiratory chain and suppresses mitochondrial dysfunction by preventing VDAC1 oligomerization [2]. VBIT-4 has been widely used in cell models to regulate mitochondrial function and oxidative stress[3].
In vitro, VBIT-4 (15μM) pretreatment for 2 hours significantly inhibited the apoptosis and mitochondrial cytochrome c release induced by staurosporine (0.2μM; 3h)[4]. Treatment with 10μM VBIT-4 for 24 hours significantly inhibited the accumulation of mitochondrial ROS, total lipid peroxide, and mitochondrial lipid peroxide in SK-Hep1 cells induced by Erastin, and suppressed ferroptosis[5].
In vivo, VBIT-4 treatment via intraperitoneal injection (20mg/kg) every other day for 4 weeks can reduce mitochondrial calcium overload in the skeletal muscles of D2.DMDel8-34 mice, enhance the resistance to permeability transition pore-induced stimuli, and improve the ultrastructure of mitochondria[6]. Oral administration of 20mg/kg dose of VBIT-4 daily for 5 months inhibited neuronal death, neuroinflammation and neuro-metabolic dysfunction in 5×FAD mice, and prevented cognitive decline[7].
References:
[1] Gorny H, Mularoni A, Delcros J G, et al. Combining nano-differential scanning fluorimetry and microscale thermophoresis to investigate VDAC1 interaction with small molecules[J]. Journal of enzyme inhibition and medicinal chemistry, 2023, 38(1): 2121821.
[2] Belosludtsev K N, Ilzorkina A I, Matveeva L A, et al. Effect of VBIT-4 on the functional activity of isolated mitochondria and cell viability[J]. Biochimica et Biophysica Acta (BBA)-Biomembranes, 2024, 1866(5): 184329.
[3] Miura S, Sekine T, Okochi S, et al. Exacerbation of Doxorubicin-Induced Mitochondrial Dysfunction by the Inhibition of Voltage-Dependent Anion Channel 1 Oligomerization[J]. Circulation, 2025, 152(Suppl_3): A4361657-A4361657.
[4] Ben-Hail D, Begas-Shvartz R, Shalev M, et al. Novel compounds targeting the mitochondrial protein VDAC1 inhibit apoptosis and protect against mitochondrial dysfunction[J]. Journal of Biological Chemistry, 2016, 291(48): 24986-25003.
[5] Oh S J, Ikeda M, Ide T, et al. Mitochondrial event as an ultimate step in ferroptosis[J]. Cell death discovery, 2022, 8(1): 414.
[6] Dubinin M V, Stepanova A E, Mikheeva I B, et al. VBIT-4 Rescues Mitochondrial Dysfunction and Reduces Skeletal Muscle Degeneration in a Severe Model of Duchenne Muscular Dystrophy[J]. International Journal of Molecular Sciences, 2025, 26(18): 8845.
[7] Verma A, Shteinfer-Kuzmine A, Kamenetsky N, et al. Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology[J]. Translational Neurodegeneration, 2022, 11(1): 58.
VBIT-4是电压依赖性阴离子通道1（VDAC1）寡聚化的抑制剂，对纯化VDAC1的Kd值为3μM[1]。VBIT-4能诱导呼吸链复合物I底物驱动的细胞器去极化，并通过阻止VDAC1寡聚化来抑制线粒体功能障碍[2]。VBIT-4已广泛应用于细胞模型中，用于调节线粒体功能和氧化应激[3]。
在体外，VBIT-4（15μM）预处理2小时显著抑制了staurosporine（0.2μM；3小时）诱导的细胞凋亡和线粒体细胞色素c释放[4]。用10μM的VBIT-4处理24小时显著抑制了Erastin诱导的SK-Hep1细胞中线粒体ROS、总脂质过氧化物和线粒体脂质过氧化物的积累，并抑制了铁死亡[5]。
在体内，VBIT-4通过腹腔注射（20mg/kg）每隔一天治疗4周，可以减少D2.DMDel8-34小鼠骨骼肌中的线粒体钙超载，增强对通透性转换孔诱导刺激的抵抗力，并改善线粒体的超微结构[6]。每日口服20mg/kg剂量的VBIT-4连续5个月，可抑制5×FAD小鼠的神经元死亡、神经炎症和神经代谢功能障碍，并防止认知能力下降[7]。