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Hydrogen sulfide (H 2 S) is a gas signaling molecule with versatile bioactivities; however, its exploitation for disease treatment appears challenging. This study describes the design and characterization of a novel type of H 2 S donor–drug conjugate (DDC) based on the thio-ProTide scaffold, an evolution of the ProTide strategy successfully used in drug discovery. The new H 2 S DDCs achieved hepatic co-delivery of H 2 S and an anti-fibrotic drug candidate named hydronidone, which synergistically attenuated liver injury and resulted in more sufficient intracellular drug exposure. The potent hepatoprotective effects were also attributed to the H 2 S-mediated multipronged intervention in lipid peroxidation both at the whole cellular and lysosomal levels. Lysosomal H 2 S accumulation and H 2 S DDC activation were facilitated by the hydrolysis through the specific lysosomal hydrolase, representing a distinct mechanism for lysosomal targeting independent of the classical basic moieties. These findings provided a novel pattern for the design of optimally therapeutic H 2 S DDC and organelle-targeting functional molecules. The thio-ProTides, as novel H 2 S donor–drug conjugates, enabled the co-delivery of H 2 S with pharmacologically active molecules. Their lysosomal H 2 S accumulation potentially enhanced the mitigation of hepatic lipotoxicity and fibrosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) is a gas signaling molecule with versatile bioactivities; however, its exploitation for disease treatment appears challenging. This study describes the design and characterization of a novel type of H2S donor–drug conjugate (DDC) based on the thio-ProTide scaffold, an evolution of the ProTide strategy successfully used in drug discovery. The new H2S DDCs achieved hepatic co-delivery of H2S and an anti-fibrotic drug candidate named hydronidone, which synergistically attenuated liver injury and resulted in more sufficient intracellular drug exposure. The potent hepatoprotective effects were also attributed to the H2S-mediated multipronged intervention in lipid peroxidation both at the whole cellular and lysosomal levels. Lysosomal H2S accumulation and H2S DDC activation were facilitated by the hydrolysis through the specific lysosomal hydrolase, representing a distinct mechanism for lysosomal targeting independent of the classical basic moieties. These findings provided a novel pattern for the design of optimally therapeutic H2S DDC and organelle-targeting functional molecules.