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

  • J Med Chem. 2026 Feb 12;69(3):3233-3251. doi: 10.1021/acs.jmedchem.5c03140.
Yujiao Qin  1 ,  Qingye Zhu  1 ,  Zhixiang Yan  2 ,  Xin Chen  3 ,  Jiacheng Wang  1 ,  Xinru Zhang  1 ,  Ruiguo Liang  1 ,  Jiaying Han  1 ,  Yi Mao  1 ,  Xianglong Wang  1 ,  Han Ju  1 ,  Jie Zhou  1 ,  Ping Li  1 ,  Mingxin Dong  1
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao 266021, China.
  • 2. School of Basic Medicine, Qingdao University, Qingdao 266021, China.
  • 3. National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
PMID: 41632558 DOI: 10.1021/acs.jmedchem.5c03140
Abstract

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.

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