Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells
Name
jacs.0c00099.pdf
Description
Published version
Size
1.44 MB
Format
Adobe PDF
Checksum (MD5)
e1a5417734f1bc9c548f999bcf0e9598
Author(s)
Goldberg, Jacob Michael
Lippard, Stephen J.
Date Issued
March 2020
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Citation
Lee, Miseon et al. “Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells.” Journal of the American Chemical Society 142 (2020): 6477-6482 © 2020 The Author(s)
Version
Final published version
Abstract
Copyright © 2020 American Chemical Society. 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.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1021/jacs.0c00099
