2. Academic Validation
  3. A Spatiotemporally Controlled and Mitochondria-Targeted Prodrug of Hydrogen Sulfide Enables Mild Mitochondrial Uncoupling for the Prevention of Lipid Deposition

A Spatiotemporally Controlled and Mitochondria-Targeted Prodrug of Hydrogen Sulfide Enables Mild Mitochondrial Uncoupling for the Prevention of Lipid Deposition

  • J Med Chem. 2024 Nov 14;67(21):19188-19199. doi: 10.1021/acs.jmedchem.4c01599.
Xian Zhang 1 2,  Mengjie Ye 1 2,  Yuxin Ge 1 2,  Can Xiao 1 2,  Keni Cui 1 2,  Qidong You 1 2,  Zhengyu Jiang 1 2,  Xiaoke Guo 1 2
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
PMID: 39441124 DOI: 10.1021/acs.jmedchem.4c01599
Abstract

Mild mitochondrial uncoupling offers therapeutic benefits for various diseases like obesity by regulating cellular energy metabolism. However, effective chemical intervention tools for inducing mild mitochondria-targeted uncoupling are limited. Herein, we have developed a mitochondria-targeted H2S prodrug M1 with a unique property of on-demand photoactivated generation of H2S accompanied by self-reporting fluorescence for real-time tracking. Upon photoirradiation, M1 decomposes in mitochondria to generate H2S and a turn-on fluorescent coumarin derivative for the visualization and quantification of H2S. M1 is confirmed to induce Reactive Oxygen Species (ROS)-dependent mild mitochondrial uncoupling, activating mitochondria-associated adenosine monophosphate-activated protein kinase (AMPK) to suppress palmitic acid (PA)-induced lipid deposition in hepatocytes. The uncoupling functions induced by M1 are strictly controlled in mitochondria, representing a fresh strategy to prevent lipid deposition and improve metabolic syndrome by increasing cellular energy expenditure.

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