title: Novel Compounds Targeting the Mitochondrial Protein VDAC1 Inhibit Apoptosis and Protect against Mitochondrial Dysfunction.
abstract: 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.
authors.affiliation: From the Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Danya
authors.initials: D
authors.lastname: Ben-Hail
authors.affiliation: From the Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Racheli
authors.initials: R
authors.lastname: Begas-Shvartz
authors.affiliation: From the Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Shalev
authors.affiliation: From the Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Shteinfer-Kuzmine
authors.affiliation: the Department of Chemistry, Bar-Ilan University, Ramat-Gan 5290002, Israel, and.
authors.forename: Arie
authors.initials: A
authors.lastname: Gruzman
authors.affiliation: the Departments of Biomedicine and Biotechnology and.|Chemical Sciences, National Institute for Biomembranes and Biosystems, Section of Catania, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Reina
authors.affiliation: the Departments of Biomedicine and Biotechnology and.
authors.forename: Vito
authors.initials: V
authors.lastname: De Pinto
authors.affiliation: From the Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel, vardasb@bgu.ac.il.
authors.forename: Varda
authors.identifier: http://orcid.org/0000-0002-6756-4340
authors.initials: V
authors.lastname: Shoshan-Barmatz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization / Q000187:drug effects / Q000235:genetics; D051381:Rats; D050995:Voltage-Dependent Anion Channel 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C494762:VDAC1 protein, human; C494763:Vdac1 protein, mouse; C494764:Vdac1 protein, rat; D050995:Voltage-Dependent Anion Channel 1
keywords: apoptosis; bioluminescence resonance energy transfer (BRET); drug development; membrane protein; mitochondria; mitochondrial apoptosis; oligomerization; small molecule; voltage-dependent anion channel (VDAC)