Trifluoroacetylated tyrosine-rich D-tetrapeptides have potent antioxidant activity

- Identification of trifluoroacetylated d-peptides with potent anti-oxidant activity.
- Tetrapeptides have the common CF3CO-tyr-tyr moiety on the N-terminal side.
- SAR studies identify CF3tyr-tyr as the core responsible of antioxidant activity.
- Structural studies suggest that activity correlates with tridimensional structure.
- Peptides protect keratinocytes from lipids peroxidation.

The term “oxidative stress” indicates a set of chemical reactions unleashed by a disparate number of events inducing DNA damage, lipid peroxidation, protein modification and other effects, which are responsible of altering the physiological status of cells or tissues. Excessive Reactive Oxygen Species (ROS) levels may accelerate ageing of tissues or induce damage of biomolecules thus promoting cell death or proliferation in dependence of cell status and of targeted molecules. In this context, new antioxidants preventing such effects may have a relevant role as modulators of cell homeostasis and as therapeutic agents. Following an approach of peptide libraries synthesis and screening by an ORACFL assay, we have isolated potent anti-oxidant compounds with well-defined structures. Most effective peptides are N-terminally trifluoroacetylated (CF3) and have the sequence tyr-tyr-his-pro or tyr-tyr-pro-his. Slight changes in the sequence or removal of the CF3 group strongly reduced antioxidant ability, suggesting an active role of both the fluorine atoms and of peptide structure. We have determined the NMR solution structures of the active peptides and found a common structural motif that could underpin the radical scavenging activity. The peptides protect keratinocytes from exogenous oxidation, thereby from potential external damaging cues, suggesting their use as skin ageing protectant and as cell surviving agents.

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