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Current thesis summarizes the work on development of novel bioluminescent probes for measurement of activity of dipeptidylpep-tidase-4 (DPP-4) and for quantification of mitochondrial membrane potential (MMP). DPP-4 enzyme plays critical role in develop-ment of diabetes mellitus type 2 and is involved in progression of cancer. Fast and efficient discovery of novel DPP-4 inhibitors is essential for a treatment of people suffering from diabetes in the world. MMP is an important indicator of mitochondria metabolic state and function. It is known that many human pathologies such as cancer, progeria, cardiovascular and neurodegenerative disor-ders are followed by mitochondria dysfunction. However, is not clear how exactly it is involved in pathogenesis of these diseases. Therefore, a better understanding of underlaying biology of these disorders may provide a path for improved treatments. Despite this pressing need, currently no efficient methodologies exist that allow non-invasive imaging and quantification of DPP-4 activity and MMP in vivo, resulting in a lack of tools for efficient screening of potential therapies. To address the unmet need we applied a novel approach based on combination of versatile click chemistry reactions with ultra-sensitive bioluminescent imaging for development of assays for non-invasive quantification of DPP-4 activity and MMP in living animals. The reported tools have several significant advantages over existing conventional methods and therefore have potential to directly impact many pathological investigations becoming a valuable tool for drug discovery.
Elena Goun, Arkadiy Bazhin, Min Chen, Ji Qi