Synthesis and antiageing properties of antioxidant pseudopeptides designed based on the bioisostere principle

Nineteen antioxidant pseudopeptides were designed and synthesized. They were confirmed as mild antioxidants, in which L1-11 was the most active antioxidant with a cellular antioxidant activity (CAA) value of 5.65 ± 0.64 μmol QE/g, and L1-12 was the second most active one (5.58 ± 0.66 μmol QE/g). The existence of nonnatural amino acids in L1-12 increased its stability. Pretreatment with L1-12 dose-dependently extended the lifespan of Caenorhabditis elegans. L1-12 improved resistance against UVB irradiation, oxidative stress induced by paraquat, and thermal shock. It decreased the reactive oxygen species level and upregulated the superoxide dismutase activity inside C. elegans. This pseudopeptide sensitively enhanced the expressions of the Cat-1 and Nhr-8 genes to reduce oxidative damage, leading to an extension of the lifespan. All the evidence support that L1-12 may probably be a potential antiageing agent.