In pursuit of feedback activation: New insights into redox-responsive hydropersulfide prodrug combating oxidative stress
Bi-Xin Xu,
Tian-Yu Hu,
Jin-Biao Du,
Tao Xie,
Ya-Wen Xu,
Xin Jin,
Si-Tao Xu,
Hao-Wen Jin,
Guangji Wang,
Jiankun Wang,
Le Zhen
Affiliations
Bi-Xin Xu
Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, Jiangsu, China
Tian-Yu Hu
Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, Jiangsu, China
Jin-Biao Du
Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, Jiangsu, China
Tao Xie
Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, Jiangsu, China
Ya-Wen Xu
Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, Jiangsu, China
Xin Jin
Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, Jiangsu, China
Si-Tao Xu
Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, Jiangsu, China
Hao-Wen Jin
Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, Jiangsu, China
Guangji Wang
Corresponding author.; Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, Jiangsu, China
Jiankun Wang
Corresponding author.; Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, Jiangsu, China
Le Zhen
Corresponding author.; Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, Jiangsu, China
Redox-responsive hydropersulfide prodrugs are designed to enable a more controllable and efficient hydropersulfide (RSSH) supply and to thoroughly explore their biological and therapeutic applications in oxidative damage. To obtain novel activation patterns triggered by redox signaling, we focused on NAD(P)H: quinone acceptor oxidoreductase 1 (NQO1), a canonical antioxidant enzyme, and designed NQO1-activated RSSH prodrugs. We also performed a head-to-head comparison of two mainstream structural scaffolds with solid quantitative analysis of prodrugs, RSSH, and metabolic by-products by LC-MS/MS, confirming that the perthiocarbamate scaffold was more effective in intracellular prodrug uptake and RSSH production. The prodrug was highly potent in oxidative stress management against cisplatin-induced nephrotoxicity. Strikingly, this prodrug possessed potential feedback activation properties by which the delivered RSSH can further escalate the prodrug activation via NQO1 upregulation. Our strategy pushed RSSH prodrugs one step further in the pursuit of efficient release in biological matrices and improved druggability against oxidative stress.
