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

ABSTRACT: The loss of insulin-producing ?-cells is the central pathological event in type 1 and 2 diabetes, which has led to efforts to identify molecules to promote ?-cell proliferation, protection, and imaging. However, the lack of ?-cell specificity of these molecules jeopardizes their therapeutic potential. A general platform for selective release of small-molecule cargoes in ?-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 ?-cells to develop a Zn(II)-based prodrug system to selectively and tracelessly deliver bioactive small molecules and fluorophores to ?-cells. The Zn(II)-targeting mechanism enriches the inactive cargo in ?-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 ?-cells.

SUBMITTER: Lee M 

PROVIDER: S-EPMC7146867 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Lee Miseon M   Maji Basudeb B   Manna Debasish D   Kahraman Sevim S   Elgamal Ruth M RM   Small Jonnell J   Kokkonda Praveen P   Vetere Amedeo A   Goldberg Jacob M JM   Lippard Stephen J SJ   Kulkarni Rohit N RN   Wagner Bridget K BK   Choudhary Amit A  

Journal of the American Chemical Society 20200316 14

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 <i>ex vivo</i> or other cell-types in an organismal context will be immensely valuable in advanc  ...[more]

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