Oxidative stress results from an imbalance between the generation of reactive oxygen species and the antioxidant defense mechanisms. In recent years, oxidative stress has been implicated in a variety of detrimental health conditions including cardiovascular diseases, neurodegenerative disorders, and other types of age-related diseases. Evidence shows that the formation of superoxide radicals is a common denominator associated with all these conditions. Considering that cardiovascular diseases are the number one cause of death globally and neurodegenerative diseases are becoming a major health burden due to the aging of the global population, it is not surprising that a great deal of interest has been shown to develop new therapeutic approaches for scavenging these dangerous radicals. Superoxide dismutases (SODs) are endogenous metalloenzymes that catalyze the dismutation of these radicals into the less toxic dioxygen and hydrogen peroxide. Thus, they play a key role in cellular protection against oxidative stress conditions. The present proposal will focus on the design, synthesis and characterization of Mn/Fe SOD peptide mimics. The working hypothesis is that by designing peptides that contain the same metal binding sites as those present in the native SODs there is potential for developing novel structural and functional SOD mimics. To this aim, different native-like protein/peptide scaffolds will be prepared. Mn and Fe binding affinities, redox potentials and SOD activity will be determined for the different constructs with the objective of obtaining crucial structure-activity-redox relationships. The completion of this research will increase our understanding of the structural basis needed for the dismutation of superoxide radicals. As this understanding evolves and is further refined, it should allow us and other research groups to make inroads in designing more effective SOD mimics.