Chemical knockdown of Keap1 and homoPROTAC-ing allergic rhinitis.
10.1016/j.apsb.2025.05.025
- Author:
Jianyu YAN
1
;
Tianyu WANG
2
;
Ruizhi YU
1
;
Lijuan XU
1
;
Hongming SHAO
1
;
Tengfei LI
2
;
Zhe WANG
2
;
Xudong CHA
2
;
Zhenyuan MIAO
1
;
Chengguo XING
3
;
Ke XU
4
;
Huanhai LIU
2
;
Chunlin ZHUANG
1
Author Information
1. The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China.
2. Department of Otolaryngology, Changzheng Hospital, Naval Medical University/Second Military Medical University, Shanghai 200003, China.
3. Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, USA.
4. Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.
- Publication Type:Journal Article
- Keywords:
Allergic rhinitis;
Degradation;
E3 ligase;
HomoPROTAC;
Keap1;
Nrf2
- From:
Acta Pharmaceutica Sinica B
2025;15(8):4137-4155
- CountryChina
- Language:English
-
Abstract:
Allergic rhinitis (AR), a globally prevalent immune-mediated inflammatory condition, is still an incurable disease. In the present study, we have validated the impact of the Kelch-like ECH associated protein 1 (Keap1)-related oxidative stress and inflammatory response in clinical AR patient peripheral blood and nasal swab samples, emphasizing the biological relevance of Keap1 and AR. Targeting Keap1 -nuclear factor erythroid 2-related factor 2 (Nrf2) related anti-oxidative stress may be effective for AR intervention. Drawing inspiration from the Keap1 homodimerization and the E3 ligase characteristics, we herein present a design of novel bivalent molecules for chemical knockdown of Keap1. For the first time, we characterized ternary complexes of Keap1 dimer and one molecule of bivalent compounds. The best bivalent molecule 8 encompasses robust capacity to degrade Keap1 as a homoPROTACKEAP1. It efficaciously suppresses inflammatory cytokines in extensively different cells, including human nasal epithelial cells. Moreover, in an AR mouse model, we confirmed that the chemical degradation induced by homoPROTACKEAP1 led to therapeutic benefits in managing AR symptoms, oxidative stress and inflammation. In summary, our findings underscore the efficacy of targeting the Keap1 system through the homoPROTAC-ing technology as an innovative and promising treatment strategy for the incurable allergic disorders.
