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 characteriza-tion of a novel type of H2S donor-drug conjugate(DDC)based on the thio-ProTide scaffold,an evolu-tion 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 ef-fects 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.
Key Laboratory of Drug Metabolism and Pharmacokinetics,Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences,China Pharmaceutical University,Nanjing 210009,China
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