Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells
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 mole...
| Main Authors: | , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
American Chemical Society (ACS)
2020
|
| Online Access: | https://hdl.handle.net/1721.1/125660 |
| _version_ | 1826202686583734272 |
|---|---|
| author | Goldberg, Jacob Michael Lippard, Stephen J. |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Goldberg, Jacob Michael Lippard, Stephen J. |
| author_sort | Goldberg, Jacob Michael |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T12:14:21Z |
| format | Article |
| id | mit-1721.1/125660 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T12:14:21Z |
| publishDate | 2020 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/1256602022-10-01T08:45:36Z Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells Goldberg, Jacob Michael Lippard, Stephen J. Massachusetts Institute of Technology. Department of Chemistry 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. National Institutes of Health (U.S.) (Grant UC4DK116255) National Institutes of Health (U.S.) (Grant R01DK113597) National Institutes of Health (U.S.) (Grant RO1 DK067536) National Institutes of Health (U.S.) (Grant GM065519) National Institute of Diabetes and Digestive and Kidney Diseases (U.S.). Integrated Islet Distribution Program (Grant UC4DK098085) 2020-06-03T18:53:39Z 2020-06-03T18:53:39Z 2020-03 2020-05-18T15:33:12Z Article http://purl.org/eprint/type/JournalArticle 0002-7863 https://hdl.handle.net/1721.1/125660 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) en https://dx.doi.org/10.1021/jacs.0c00099 Journal of the American Chemical Society Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf American Chemical Society (ACS) ACS |
| spellingShingle | Goldberg, Jacob Michael Lippard, Stephen J. Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells |
| title | Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells |
| title_full | Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells |
| title_fullStr | Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells |
| title_full_unstemmed | Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells |
| title_short | Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells |
| title_sort | native zinc catalyzes selective and traceless release of small molecules in β cells |
| url | https://hdl.handle.net/1721.1/125660 |
| work_keys_str_mv | AT goldbergjacobmichael nativezinccatalyzesselectiveandtracelessreleaseofsmallmoleculesinbcells AT lippardstephenj nativezinccatalyzesselectiveandtracelessreleaseofsmallmoleculesinbcells |