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

Lee M, Maji B, Manna D, Kahraman S, Elgamal RM, Small J, Kokkonda P, Vetere A, Goldberg JM, Lippard SJ, et al. Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells. Journal of the American Chemical Society. 2020;142(14):6477–6482.

Abstract

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.

Last updated on 08/30/2021
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