Thio-ProTide strategy: A novel H2S donor-drug conjugate (DDC) alleviates hepatic injury via innate lysosomal targeting.
10.1016/j.apsb.2024.10.017
- Author:
Haowen JIN
1
;
Jie MA
1
;
Bixin XU
1
;
Sitao XU
1
;
Tianyu HU
1
;
Xin JIN
1
;
Jiankun WANG
1
;
Guangji WANG
1
;
Le ZHEN
1
Author Information
1. 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.
- Publication Type:Journal Article
- Keywords:
Cellular pharmacokinetics;
Drug conjugate;
Hydrogen sulfide donor;
Lipid peroxidation;
Liver fibrosis;
Lysosomal targeting;
ProTide prodrug;
Prodrug activation
- From:
Acta Pharmaceutica Sinica B
2024;14(12):5341-5356
- CountryChina
- Language:English
-
Abstract:
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.
