Thio-ProTide strategy: A novel HS donor-drug conjugate (DDC) alleviates hepatic injury innate lysosomal targeting.

Hydrogen sulfide (HS) 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 HS donor-drug conjugate (DDC) based on the thio-ProTide scaffold, an evolution of the ProTide strategy successfully used in drug discovery. The new HS DDCs achieved hepatic co-delivery of HS 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 HS-mediated multipronged intervention in lipid peroxidation both at the whole cellular and lysosomal levels. Lysosomal HS accumulation and HS 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 HS DDC and organelle-targeting functional molecules.