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Designing metallopeptides for the removal of superoxide radicals

Final Report Summary - MFROSPEP (Designing metallopeptides for the removal of superoxide radicals)

Oxidative stress results from an imbalance between the generation of reactive oxygen species and antioxidant defense mechanisms. Superoxide radicals, formed following a one-electron reduction of molecular oxygen, are one of the most toxic reactive oxygen species and their damaging effects lead to a variety of detrimental health conditions including cardiovascular diseases, neurodegenerative disorders, and other types of age-related diseases. Considering that cardiovascular diseases are the number one cause of death globally and that neurodegenerative diseases are becoming a major global health burden, particularly with the aging of the global population, research into these disorders is of great importance. Indeed, one of the major concerns raised by the ERA under the FP7 program was the need for new therapies to battle cardiovascular diseases and neurodegenerative disorders to improve the health of European citizens.

Superoxide dismutases are endogenous metalloenzymes that catalyze the dismutation of the superoxide radicals into the less toxic dioxygen and hydrogen peroxide. Thus, they play a key role in cellular protection against oxidative stress conditions. Not surprisingly, there has been and there is a great deal of interest in the chemistry community to develop novel and better antioxidant compounds that can react with superoxide radicals and efficiently replicate the activity of the native SOD metalloenzymes. Under these grounds, following Nature’s lead we have been designing and studying different peptide frameworks capable of binding redox active metal ions with the ultimate goal of achieving SOD activity under physiological conditions. We obtained very promising scaffolds which can be prepared with different degrees of flexibility allowing the metal ion redox cycling needed for the catalytic removal of superoxide radicals. We think we are on the right direction and we hope that this research and its continuation at the CNRS in France (which will also include in vivo experiments) will suggest possible peptidic systems that can be used as starting points for the development of artificial SOD peptides with potentially therapeutic applications in the broad range of diseases resulting from oxidative stress.