It is well established that a high mitochondrial membrane potential is a major driving force for the generation of free radicals from the mitochondria. Numerous experiments have demonstrated that a decrease in the membrane potential of less than 20% would decrease free radical production by up to 90% without disrupting the normal metabolic production of energy (ATP). This is supported by published scientific data. By targeting a protein embedded in the mitochondrial inner membrane, we believe that we can controllably and safely modulate the mitochondrial membrane potential thus decreasing free radical production. This approach is novel and does not involve scavenging free radicals after their production.

We selected 80 promising compounds to explore the structural activity relationship of the mitochondrial target protein and their ability to decrease mitochondrial membrane potential, thereby drastically decreasing the production of free radicals. Three of these compounds decreased global reactive oxygen species production in vitro. This confirms that it is possible to lower free radical production in cell culture without significantly disrupting ATP production and cell viability. The next stage is the synthesis of drugs/pro-drugs from our 3 compounds by linking them to mitochondrial membrane permeable ligands (parent carrier). This will deliver the active part of the pro-drug into the mitochondrial matrix, where it will be cleaved from the parent carrier by the action of mitochondrial enzymes. The active compound will then be free to react with the target protein. This will be screened in animal cell models to look for a reduction in oxidative damage. This stage of the research is underway and should be complete by December 2020.