Stapled Peptides with Therapeutic Potential for Ischemic Stroke by Blocking the Endocytosis of GluA2 AMPAR

Targeting the interaction between the C-terminal domain of the GluA2 subunit of AMPA receptors and BRAG2 presents a highly promising therapeutic approach for acute ischemic stroke. The membrane-permeable peptide Tat-GluA2-3Y has shown potential by competitively binding to BRAG2 to inhibit GluA2 endocytosis; however, its clinical application is limited due to poor stability in vivo. To address this limitation, we developed stapled peptides based on GluA2-3Y, leading to the identification of the lead compound P3LC7LC-P, which exhibits high-affinity binding to BRAG2. Functionally, P3LC7LC-P offers strong neuroprotection in two injury models: oxygen-glucose deprivation-induced and glutamate-induced neurotoxicity. Notably, P3LC7LC-P significantly improved plasma stability compared to Tat-GluA2-3Y, with a half-life exceeding 372.7 min. In the transient middle cerebral artery occlusion (tMCAO) model, P3LC7LC-P reduced cerebral infarction areas to 21.00% at a dose of 8 mg/kg. These findings highlight P3LC7LC-P as a promising candidate for the development of novel therapies for ischemic stroke.