SSK1, a β-Galactosidase-targeted Prodrug, Attenuates Inflammation

β-Galactosidase, a glycoside hydrolase family, catalyzes the cleavage of glycosidic bonds β-Galactoside is hydrolyzed to monosaccharide. Specifically, β-Galactosidase is a kind of exoglycosidase, which can hydrolyze the protein formed between galactose and its organic part β-Glycosidic bond. Besides, it is an essential enzyme for the human body. β-Galactosidase has three enzyme activities. First, it can cleave disaccharide lactose to form glucose and galactose, and then enter glycolysis. Secondly, the enzyme can catalyze the transgalactosylation of lactose to isolactose. And thirdly, isolactose can be cleaved to monosaccharide. Moreover, isolactose binds to lacZ repressor and produces a positive feedback loop to regulate the expression of the amount of β-Galactosidase in cells.

Furthermore, β-Galactosidase is important to organisms because it is a key provider of energy production. Meanwhile, β-Galactosidase is also a carbon source by decomposing lactose into galactose and glucose. In recent years, β-Galactosidase has been studied as a potential therapy for lactose intolerance. Here, we will introduce a β-Galactosidase-targeted prodrug attenuates inflammation, SSK1.

SSK1 is a β-Galactosidase-targeted Prodrug Attenuates Inflammation.

First of all, SSK1 is a senescence-specific killing compound. SSK1 is activated by lysosomal β-galactosidase. Nonetheless, SSK1 selectively killed senescent cells through the activation of p38 MAPK and induction of apoptosis.

In the second place, SSK1 with 0.5 µM for 12-72 hours activates the phosphorylation levels of both p38 MAPK and MKK3/MKK6 in senescent cells. Interestingly, SSK1 kills senescent cells through the activation of the p38 MAPK signaling pathway. Importantly, SSK1 is able to induce mitochondrial DNA damage in senescent cells. Particularly, SSK1 selectively and potently eliminates β-galactosidase -positive senescent cells within a wide therapeutic window.

Last but not the least, SSK1 with 0.5 mg/kg by i.p. two days every week for four weeks could eliminate senescent cells. Obviously, SSK1 decrease senescence-associated markers in lung-injured mice. In aged mice (20-month-old), SSK1 effectively clears senescent cells in different tissues. SSK1 decreased the senescence- and age-associated gene signatures. Additionally, SSK1 attenuates low-grade local and systemic inflammation, and restores physical function.

All in all, SSK1 is a β-Galactosidase-targeted prodrug attenuates inflammation.


Yusheng Cai, et al. Cell Res. 2020 Jul;30(7):574-589.