Novel compounds targeting the mitochondrial protein VDAC1 inhibit apoptosis and protect against mitochondria dysfunction

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 mitochondria-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 and concomitant with an inhibition of apoptosis as induced by various means and in various cell lines. The compounds protected against apoptosis-associated mitochondria dysfunction, restoring dissipated mitochondria membrane potential, and thus cell energy and metabolism, decreasing ROS production, and preventing 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 mitochondria dysfunction. The compounds VBIT-3 and VBIT-4 thus offer a therapeutic strategy for treating different diseases associated with enhanced apoptosis and points to VDAC1 as a promising target for therapeutic intervention.