Identification of a Small Molecule Cyclophilin D Inhibitor for Rescuing Aβ-Mediated Mitochondrial Dysfunction

Cyclophilin D (CypD), a peptidylprolyl isomerase F (PPIase), plays a central role in opening the mitochondrial membrane permeability transition pore leading to cell death. CypD resides in the mitochondrial matrix, associates with the inner mitochondrial membrane, interacts with amyloid beta to exacerbate mitochondrial and neuronal stress and has been linked to Alzheimer's disease (AD). We report the biological activity of a small-molecule CypD inhibitor (C-9), which binds strongly to CypD and attenuates mitochondrial and cellular perturbation insulted by Aβ and calcium stress. Binding affinities for C-9 were determined using in vitro surface plasmon resonance. This compound antagonized calcium-mediated mitochondrial swelling, abolished Aβ-induced mitochondrial dysfunction as shown by increased cytochrome c oxidase activity and adenosine-5'-triphosphate levels, and inhibited CypD PPIase enzymatic activity by real-time fluorescence capture assay using Hamamatsu FDSS 7000. Compound C-9 seems a good candidate for further investigation as an AD drug.