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  2. First-generation species-selective chemical probes for fluorescence imaging of human senescence-associated β-galactosidase

First-generation species-selective chemical probes for fluorescence imaging of human senescence-associated β-galactosidase

  • Chem Sci. 2020 Jun 17;11(28):7292-7301. doi: 10.1039/d0sc01234c.
Xiaokang Li 1 Wenjing Qiu 1 Jinwen Li 1 Xi Chen 2 Yulu Hu 2 Ying Gao 2 Donglei Shi 1 Xinming Li 1 Huiling Lin 1 Zelan Hu 1 Guoqiang Dong 3 Chunquan Sheng 3 Bei Jiang 4 Conglong Xia 4 Chu-Young Kim 5 Yuan Guo 2 Jian Li 1 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology Shanghai 200237 China jianli@ecust.edu.cn.
  • 2 Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry and Materials Science, Northwest University Xi'an 710127 China guoyuan@nwu.edu.cn.
  • 3 School of Pharmacy, Second Military Medical University Shanghai 200433 China.
  • 4 Institute of Materia Medica, College of Pharmacy and Chemistry, Dali University Dali 671000 China.
  • 5 Department of Chemistry and Biochemistry, The University of Texas at El Paso El Paso Texas 79968 USA.
Abstract

Human senescence-associated β-galactosidase (SA-β-gal), the most widely used biomarker of aging, is a valuable tool for assessing the extent of cell 'healthy aging' and potentially predicting the health life span of an individual. Human SA-β-gal is an endogenous lysosomal Enzyme expressed from GLB1, the catalytic domain of which is very different from that of E. coli β-gal, a Bacterial enzyme encoded by lacZ. However, existing chemical probes for this marker still lack the ability to distinguish human SA-β-gal from β-gal of other species, such as Bacterial β-gal, which can yield false positive signals. Here, we show a molecular design strategy to construct fluorescent probes with the above ability with the aid of structure-based steric hindrance adjustment catering to different Enzyme pockets. The resulting probes normally work as traditional SA-β-gal probes, but they are unique in their powerful ability to distinguish human SA-β-gal from E. coli β-gal, thus achieving species-selective visualization of human SA-β-gal for the first time. NIR-emitting fluorescent probe KSL11 as their representative further displays excellent species-selective recognition performance in biological systems, which has been herein verified by testing in senescent cells, in lacZ-transfected cells and in E. coli-β-gal-contaminated tissue sections of mice. Because of our probes, it was also discovered that SA-β-gal content in mice increased gradually with age and SA-β-gal accumulated most in the kidneys among the main organs of naturally aging mice, suggesting that the kidneys are the organs with the most severe aging during natural aging.

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