Design and Optimization of Lysosome-Targeted β-Galactoside Senolytic Prodrugs: Harnessing the Aromatic Ring of Self-Immolative Linkers

  • J Med Chem. 2026 Apr 23;69(8):8739-8762. doi: 10.1021/acs.jmedchem.5c01922.
Jie Liu  1 ,  Xiaoke Liu  1 ,  Haitian Fu  2 ,  Chunjing Yu  2 ,  Jing Hu  3 ,  Junjie Fu  1  4 ,  Jian Yin  1  4
Affiliations
  • 1. Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology & School of Life Sciences and Health Engineering, Jiangnan University, Lihu Avenue 1800, Wuxi, Jiangsu 214122, China.
  • 2. Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University, Wuxi 214122, China.
  • 3. Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China.
  • 4. Innovation Center for Vaccine Engineering, Jiangnan University, Wuxi 214122, China.
PMID: 41875331 DOI: 10.1021/acs.jmedchem.5c01922
Abstract

To improve senolytic efficacy and selectivity, we designed gemcitabine (Gem)-based galactoside prodrugs activated by senescence-associated β-galactosidase (SA-β-gal), bearing lysosome-targeting groups at the 3- and 5-positions of the self-immolative linker aromatic ring. This strategy avoids stereocenter formation and promotes faster, electron-donating-effect-driven drug release. Gal-dMor-Gem, with two morpholine groups, showed the strongest activity. Its senolytic index reached 16.1-56.7 across six senescent cell (SnC) models, a 2.8- to 3.7-fold improvement over the nontargeted SSK1. Gal-dMor-Gem released Gem faster and preferentially induced SnC Apoptosis, as validated in a coculture model. Biodistribution studies confirmed its preferential accumulation and activation in senescent tissues. In senescent mice, Gal-dMor-Gem (0.5 mg/kg) surpassed SSK1 in restoring body weight, improving biochemical parameters, and reducing SA-β-gal, IL-6, and lamin B1 abnormalities in multiple organs. At 1.0 mg/kg, most markers returned to healthy levels. This work identifies Gal-dMor-Gem as a potent senolytic and highlights a generalizable strategy for developing targeted SA-β-gal-responsive prodrugs.

Products