Rational Design of Dual-Targeting Novel GPE-Derived Oligopeptide Conjugates for Alzheimer’s Disease: Synergistic Inhibition of Excitotoxicity and Oxidative Stress

Alzheimer’s disease (AD) presents a critical therapeutic gap, necessitating novel multitarget strategies. Excitotoxicity via NMDA receptor overactivation and oxidative stress is a key driver of Tau hyperphosphorylation and neuronal loss. While the tripeptide Gly-Pro-Glu (GPE) derived from IGF-1 exhibits NMDA receptor antagonism, its clinical potential is limited by poor blood–brain barrier penetration and rapid hydrolysis. Herein, we rationally designed three novel GPE-derived oligopeptide conjugates (SAC-PE, SPE, and SAR-SPE) by replacing the N-terminal glycine with antioxidant moieties (( S )-allyl- l -cysteine or thioproline derivatives) while preserving the active C-terminal Pro-Glu (PE) dipeptide core. This design aimed to confer dual-targeting capabilities against both excitotoxicity and oxidative stress. Among them, SAC-PE demonstrated superior properties, including the highest calculated lipophilicity and excellent cellular safety. In Aβ 1–42 -stimulated HT-22 hippocampal neurons, SAC-PE effectively scavenged reactive oxygen species (ROS), released endogenous H 2 S, and significantly reduced p-Tau and p-CaMKII levels while upregulating the expression of the neurotrophic factor BDNF, synaptic proteins (SYN, PSD-95) and the antioxidant regulator Nrf2, outperforming GPE. In AD model mice, SAC-PE administration robustly improved cognitive deficits in Morris water maze (MWM), novel object recognition, and passive avoidance tests. Molecular and histological analyses confirmed its superior efficacy in reducing hippocampal p-Tau and p-CaMKII levels, enhancing Nrf2 expression, and preventing neuronal loss compared with GPE. These findings establish SAC-PE as a promising dual-targeting therapeutic candidate that synergistically inhibits excitotoxicity and oxidative stress, offering a novel strategic approach for AD modification.