MFROSPEP

Designing metallopeptides for the removal of superoxide radicals

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Superoxide radicals are a common denominator in many disorders. To increase the antioxidant defence mechanisms, European researchers generated artificial enzymes that mimicked endogenous processes.

Descrizione progetto (Article)

Cardiovascular diseases are still the number one cause of death and neurodegenerative disorders are becoming a major global health burden particularly with the ageing of the population. Oxidative stress, originating from an imbalance between the generation of reactive oxygen species and the antioxidant defence mechanisms of cells, has been implicated in these diseases and evidence shows that a common denominator are superoxide radicals.

Given the prevalence of these diseases among the European population, the EU-funded 'Designing metallopeptides for the removal of superoxide radicals' (MFROSPEP) project aimed to find new therapeutic solutions. Researchers therefore decided to mimic the natural processes that take place within cells to fight against the detrimental effects of oxidative stress conditions.

Cells possess superoxide dismutases (SODs), endogenous metalloenzymes that convert superoxide radicals into the less toxic dioxygen and hydrogen peroxide. The MFROSPEP project aimed to replicate this process, known as dismutation, by developing novel and better antioxidant compounds. In this context, they formulated promising peptide scaffolds capable of binding redox active metal ions under physiological conditions. Their degrees of flexibility allowed the metal ion redox cycling needed for the catalytic removal of superoxide radicals and therefore, these metallopeptide systems showed potential to evolve as SOD mimics.

Overall, the MFROSPEP research increased our understanding of the key factors needed to develop antioxidant agents. The generated peptide systems will form the basis for the development of artificial SOD enzymes for therapeutic applications against cardiovascular and neurodegenerative disorders. Considering the economic health burden associated with neurodegeneration, implementation of the MFROSPEP deliverables could ameliorate part of the disease phenotype.