Single amino acid substitution analogs of marine antioxidant peptides with membrane permeability exert a marked protective effect against ultraviolet-B induced damage

Ultraviolet-B (UVB) causes oxidative stress, which is implicated in skin damage and photoaging. Antioxidant peptides exhibit protective effects against UVB-induced oxidative stress and are thus regarded as potential competitors compared to synthetic antioxidants for cosmetics. In the present study, we provided a discovery pipeline for screening and modifying marine-derived antioxidant peptides, and successfully identified and characterized three novel modified peptides (WP5, LW5 and YY6) with strong antioxidant abilities. Their scavenging activities on 2,2′-azinobis-(3-ethylbenzthiazoline-6-sulphonate) radical (ABTS·) and hydroxyl radical (·OH) were higher than those of glutathione (GSH) (ABTS·: 71.12 ± 3.58 %, 67.63 ± 1.65 % and 68.51 ± 0.54 % by WP5, LW5 and YY6, respectively, vs 61.51 ± 1.02 % by GSH; ·OH: 52.15 ± 1.99 %, 51.25 ± 1.29 % and 53.06 ± 2.23 % by WP5, LW5 and YY6, respectively, vs 42.69 ± 1.18 % by GSH). The modified peptides can effectively penetrate cell membrane and significantly enhance cell viability against UVB-induced oxidative stress in human keratinocyte (HaCaT) cells by reducing the levels of reactive oxygen species and malondialdehyde and increasing the activity of intracellular antioxidant enzymes, including superoxide dismutase and glutathione peroxidase. Additionally, the modified peptides decreased the expression of tumor necrosis factor-α, interleukin-6 and interleukin-1β in UVB-induced cell inflammatory response, exhibiting a potent anti-inflammatory activity. Further investigation into the molecular mechanism revealed that the modified peptides not only decreased cell apoptosis by down-regulating the apoptosis factors Bax/Bcl-2 and c-PARP, but also increased the antioxidant capacity of HaCaT cells by interrupting the interaction between Kelch-like ECH associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2), and ultimately promoting Nrf2 activation. The findings suggest a promising strategy for accelerating the discovery of antioxidant peptides and cell-penetrating peptides, providing valuable insights for pharmaceutical and cosmetic industries.