Journal Article Epublish
PubMed: 40454347 DOI: 10.1021/acscentsci.5c00023
Unraveling Small Molecule-Mediated Sirtuin 3 Activation at a Distinct Binding Site for Cardioprotective Therapies.
ACS Cent Sci 11(5):704-718
Authors: Dan Zhang, Jifa Zhang, Chengyong Wu, Yao Xiao, Liwei Ji, Jiarui Hu, Jianjun Ding, Tao Li, Yiwen Zhang, Liang Ouyang
Affiliations
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
- Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, Jiangsu, China.
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, Sichuan, China.
Abstract
Sirtuin 3 (SIRT3), a pivotal mitochondrial deacetylase, plays a critical role in restoring mitochondrial function, particularly through the activation of autophagy. Despite its promise as a cardioprotective target, developing SIRT3 activators and their therapeutic applications remains challenging. Here, we report the identification of SKLB-11A, a SIRT3 activator with submicromolar affinity and high efficacy. Structural and mutagenesis analyses revealed a unique allosteric site for SKLB-11A in SIRT3, where a conformational change in Leu298 drives its potent activation. Subsequent studies demonstrated that SKLB-11A drives autophagy/mitophagy signaling pathways, effectively preventing mitochondrial dysfunction, and improving cardiac dysfunction in both doxorubicin (Dox)-induced cardiotoxicity and myocardial ischemia/reperfusion (I/R) models. Collectively, our data highlight the potential of pharmacological SIRT3 activation as an effective therapeutic strategy for cardioprotection. SKLB-11A, as a first-in-class SIRT3 allosteric activator with a distinct binding mode, not only offers a valuable tool for exploring the physiological and pathological roles of SIRT3 deacetylation but also holds promise for the development of targeted cardioprotective therapies.
MeSH
Autophagy, Sirtuins, Sirtuin 3, Therapeutics, Small Molecules