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Compounds Targeting the Mitochondrial Protein VDAC1: A Therapeutic Strategy in Neurodegenerative Diseases



Voltage-dependent anion channel (VDAC) is a multi-functional protein that mediates the fluxes of nucleotides and metabolite, hemes, cholesterol and ions, including Ca2+, across the outer mitochondrial membrane (OMM). VDAC1 is considered as a hub protein, interacting with over 150 proteins that regulate the integration of mitochondrial functions with other cellular activities. Thus, VDAC1 serves as a mitochondrial gatekeeper, controlling metabolic and energetic cross-talk between mitochondria and the rest of the cell and a key player in mitochondria-mediated apoptosis. Impaired mitochondrial function has been proposed as a causative factor in neurodegenerative diseases, such as Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and Alzheimer’s disease (AD). Mitochondria occupy a central position in cell life and death, with mitochondrial dysfunction having been implicated in AD. VDAC, located in the mitochondria and also found in the cell membrane, is involved in AD pathogenesis via its over-expression in AD patients’ neurons. As VDAC1 over-expression was shown to lead to apoptotic cell death, and VDAC1 is overexpressed in neurodegenerative disease as AD, it is a logical target via novel small molecules.  


The Technology


VBIT-4 and VBIT-12 are novel small molecules specifically interfering with VDAC1 pro-apoptotic action and prevented apoptosis and associated processes, with no effect on naïve cells under physiological conditions. VBIT-4 was found to improve cognitive, learning and memory performance in an AD-like transgenic mouse model. A single dose toxicity study for VBIT-4 and VBIT-12 in rats showed no treatment-related mortality or clinical signs, no significant changes in hematology or in serum chemistry parameters. Initial VBIT-4 profile analysis presented an elimination half-life (PK) of 7.6 h, a stable metabolic profile and moderate intestinal permeability. Moreover, VBIT-4 showed high plasma protein binding with the bound compound fraction possibly serving as a reservoir from which slow release occurs. 




  • Prof. Shoshan-Barmatz is a leader in the research of VDAC1.
  • VBIT-4 and VBIT-12, has shown  initial preclinical proof of concept for safety and efficacy.
  • Anti-VDAC1 small molecule in AD is a novel strategy to protect against neuronal cell death. It could pave the way for more effective therapies for AD and other neurodegenerative diseases.


Patent Status


Number of PCT applications were filed (PCT/IL2006/001176, PCT/IL2016/051215 and PCT/IL2019/051181)
Granted patents in USA, Europe and Israel


Principal Investigator


Prof. Varda Shoshan-Barmatz, NIBN and the Department of Life Sciences, Ben-Gurion University of the Negev, Israel