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.

中文翻译：

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追求反馈激活：氧化还原响应性氢过硫化物前药对抗氧化应激的新见解


氧化还原响应型过硫化物前药旨在实现更可控、更高效的过硫化物 (RSSH) 供应，并彻底探索其在氧化损伤中的生物和治疗应用。为了获得氧化还原信号触发的新激活模式，我们关注 NAD(P)H：醌受体氧化还原酶 1 (NQO1)，一种典型的抗氧化酶，并设计了 NQO1 激活的 RSSH 前药。我们还对两种主流结构支架进行了头对头比较，并通过 LC-MS/MS 对前药、RSSH 和代谢副产物进行了固体定量分析，证实过硫代氨基甲酸酯支架在细胞内前药摄取和 RSSH 方面更有效生产。该前药在针对顺铂诱导的肾毒性的氧化应激管理方面非常有效。引人注目的是，这种前药具有潜在的反馈激活特性，所传递的 RSSH 可以通过 NQO1 上调进一步增强前药激活。我们的策略推动 RSSH 前药在生物基质中高效释放和提高抗氧化应激的成药性方面更进一步。