Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells

J Am Chem Soc. 2020 Apr 8;142(14):6477-6482. doi: 10.1021/jacs.0c00099. Epub 2020 Mar 16.


The loss of insulin-producing β-cells is the central pathological event in type 1 and 2 diabetes, which has led to efforts to identify molecules to promote β-cell proliferation, protection, and imaging. However, the lack of β-cell specificity of these molecules jeopardizes their therapeutic potential. A general platform for selective release of small-molecule cargoes in β-cells over other islet cells ex vivo or other cell-types in an organismal context will be immensely valuable in advancing diabetes research and therapeutic development. Here, we leverage the unusually high Zn(II) concentration in β-cells to develop a Zn(II)-based prodrug system to selectively and tracelessly deliver bioactive small molecules and fluorophores to β-cells. The Zn(II)-targeting mechanism enriches the inactive cargo in β-cells as compared to other pancreatic cells; importantly, Zn(II)-mediated hydrolysis triggers cargo activation. This prodrug system, with modular components that allow for fine-tuning selectivity, should enable the safer and more effective targeting of β-cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / metabolism*
  • Catalysis
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / physiopathology
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Humans
  • Zinc / therapeutic use*


  • Zinc