Identification and Mechanistic Study of a Novel Keap1-Targeting Antioxidant Peptide From Ulva prolifera Protein.
Zhu Shaohui, Liu Shanglian, Yao Huashan, Fang Lan, Xu Hongbo, Li Zhiyong
Abstract
Activating Nrf2 by targeting the Keap1-Nrf2 signaling axis has emerged as a viable therapeutic approach for managing oxidative stress and its associated disorders. This study employed virtual digestion, ADMET profiling, and molecular docking to identify antioxidant peptides derived from Ulva prolifera protein. A novel tetrapeptide (WDGL) was ultimately discovered, demonstrating favorable aqueous solubility, non-toxicity, high intestinal absorption efficiency, and blood-brain barrier permeability. WDGL established four H-bond interactions with some key sites of Keap1 (Arg380, Arg415, Ile416, Leu365). Besides, WDGL reduces ABTS·+ and ferric-tripyridyltriazine (Fe3+-TPTZ) in vitro and promotes the expression of GSH-Px while increasing GSH-Px and SOD enzyme activity to eliminate ROS in LPS-treated EA.hy926 cells. Furthermore, this peptide could reduce the content of ROS and ET-1 in Ang II-induced EA.hy926 cells. The result suggested that WDGL may alleviate EA.hy926 oxidative damage by activating the Keap1-Nrf2 signaling pathway.
Key Findings
- A novel tetrapeptide (WDGL) derived from Ulva prolifera protein was identified with favorable pharmacokinetic properties including aqueous solubility, non-toxicity, high intestinal absorption, and blood-brain barrier permeability.
- WDGL interacts with key Keap1 residues (Arg380, Arg415, Ile416, Leu365) through four hydrogen bonds, suggesting a mechanism for activating the Keap1-Nrf2 signaling pathway.
- WDGL demonstrated antioxidant activity by reducing ABTS·+ and Fe3+-TPTZ in vitro, enhancing GSH-Px expression and activity, increasing SOD enzyme activity, and reducing ROS and ET-1 levels in LPS- and Ang II-treated EA.hy926 cells.
Clinical Significance
The novel peptide WDGL may serve as a potential therapeutic agent to alleviate oxidative stress-related vascular endothelial damage by activating the Keap1-Nrf2 pathway, offering promise for managing oxidative stress-associated disorders.
Citation
Zhu Shaohui, Liu Shanglian, Yao Huashanet al.. Identification and Mechanistic Study of a Novel Keap1-Targeting Antioxidant Peptide From Ulva prolifera Protein. Journal of peptide science : an official publication of the European Peptide Society. 2026-Jun.