2. Academic Validation
  3. Discovery of a novel Xanthone derivative P24 for anti-AD via targeting sTGFBR3

Discovery of a novel Xanthone derivative P24 for anti-AD via targeting sTGFBR3

  • Eur J Med Chem. 2024 Oct 5:276:116729. doi: 10.1016/j.ejmech.2024.116729.
Lijun Zhou 1,  Zhentong Qi 2,  Xinpeng Wang 3,  Zhenshu Li 3,  Wenzhen Feng 2,  Nan Wang 4,  Xinzhu Li 2,  Xinyue Ning 2,  Yu Xing 2,  Xiaowen Jiang 5,  Zihua Xu 6,  Qingchun Zhao 7
Affiliations

Affiliations

  • 1 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
  • 2 Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
  • 3 Department of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China.
  • 4 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China.
  • 5 School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. Electronic address: jiangxiaowen@syphu.edu.cn.
  • 6 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. Electronic address: xuzihua-668585@163.com.
  • 7 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China; Department of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China. Electronic address: zhaoqingchun1967@163.com.
PMID: 39088998 DOI: 10.1016/j.ejmech.2024.116729
Abstract

Soluble transforming growth factor beta receptor 3 (sTGFBR3) antagonist is a new focus in the research and development of Alzheimer's disease (AD) drugs. Our previous studies have identified sTGFBR3 as a promising new target for AD, with few targeted antagonists identified. In this study, we performed structural modeling of sTGFBR3 using AlphaFold2, followed by high-throughput virtual screening and surface plasmon resonance assays. which collectively identified Xanthone as potential compounds for targeting sTGFBR3. After optimizing the sTGFBR3-Xanthone complex using molecular dynamics (MD) simulations, we prepared a series of novel Xanthone derivatives and evaluated their anti-inflammatory activity, toxicity, and structure-activity relationship in BV2 cell model induced by lipopolysaccharides (LPS) or APP/PS1/tau mouse brain extract (BE). Several derivatives with the most potent anti-inflammatory activity were tested for blood-brain barrier permeability and sTGFBR3 affinity. Derivative P24, selected for its superior properties, was further evaluated in vitro. The results indicated that P24 increased the activation of TGF-β signaling and decreased the activation of IκBα/NF-κB signaling by targeting sTGFBR3, thereby regulating the inflammation-phagocytosis balance in microglia. Moreover, the low acute toxicity, long half-life, and low plasma clearance of P24 suggest that it can be sustained in vivo. This property may render P24 a more effective treatment modality for chronic diseases, particularly AD. The study demonstrates P24 serve as potential novel candidates for the treatment of AD via antagonizing sTGFBR3.

Keywords

Alzheimer's disease; BV2 cells; Xanthone derivatives; sTGFBR3.

Figures
Products