A potent phosphodiester Keap1-Nrf2 protein-protein interaction inhibitor as the efficient treatment of Alzheimer's disease
Yi Sun,
Lijuan Xu,
Dongpeng Zheng,
Jue Wang,
Guodong Liu,
Zixin Mo,
Chao Liu,
Wannian Zhang,
Jianqiang Yu,
Chengguo Xing,
Ling He,
Chunlin Zhuang
Affiliations
Yi Sun
Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
Lijuan Xu
School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
Dongpeng Zheng
Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
Jue Wang
Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
Guodong Liu
The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
Zixin Mo
Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
Chao Liu
Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
Wannian Zhang
School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
Jianqiang Yu
School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China
Chengguo Xing
Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA
Ling He
Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China; Corresponding author.
Chunlin Zhuang
School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University, Shanghai, 200433, China; Corresponding author. School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.
The Keap1-Nrf2 pathway has been established as a therapeutic target for Alzheimer's disease (AD). Directly inhibiting the protein-protein interaction (PPI) between Keap1 and Nrf2 has been reported as an effective strategy for treating AD. Our group has validated this in an AD mouse model for the first time using the inhibitor 1,4-diaminonaphthalene NXPZ-2 with high concentrations. In the present study, we reported a new phosphodiester containing diaminonaphthalene compound, POZL, designed to target the PPI interface using a structure-based design strategy to combat oxidative stress in AD pathogenesis. Our crystallographic verification confirms that POZL shows potent Keap1-Nrf2 inhibition. Remarkably, POZL showed its high in vivo anti-AD efficacy at a much lower dosage compared to NXPZ-2 in the transgenic APP/PS1 AD mouse model. POZL treatment in the transgenic mice could effectively ameliorate learning and memory dysfunction by promoting the Nrf2 nuclear translocation. As a result, the oxidative stress and AD biomarker expression such as BACE1 and hyperphosphorylation of Tau were significantly reduced, and the synaptic function was recovered. HE and Nissl staining confirmed that POZL improved brain tissue pathological changes by enhancing neuron quantity and function. Furthermore, it was confirmed that POZL could effectively reverse Aβ-caused synaptic damage by activating Nrf2 in primary cultured cortical neurons. Collectively, our findings demonstrated that the phosphodiester diaminonaphthalene Keap1-Nrf2 PPI inhibitor could be regarded as a promising preclinical candidate of AD.
