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  • Zinc-Chelating Small Molecules Preferentially Accumulate and Function within Pancreatic β Cells.

Zinc-Chelating Small Molecules Preferentially Accumulate and Function within Pancreatic β Cells.

Cell chemical biology (2018-12-12)
Timothy M Horton, Paul A Allegretti, Sooyeon Lee, Hannah P Moeller, Mark Smith, Justin P Annes
ABSTRACT

Diabetes is a hyperglycemic condition characterized by pancreatic β-cell dysfunction and depletion. Whereas methods for monitoring β-cell function in vivo exist, methods to deliver therapeutics to β cells are lacking. We leveraged the rare ability of β cells to concentrate zinc to preferentially trap zinc-binding molecules within β cells, resulting in β-cell-targeted compound delivery. We determined that zinc-rich β cells and islets preferentially accumulated TSQ (6-methoxy-8-p-toluenesulfonamido-quinoline) in a zinc-dependent manner compared with exocrine pancreas. Next, we asked whether appending a zinc-chelating moiety onto a β-cell replication-inducing compound was sufficient to confer preferential β-cell accumulation and activity. Indeed, the hybrid compound preferentially accumulated within rodent and human islets in a zinc-dependent manner and increased the selectivity of replication-promoting activity toward β cells. These data resolve the fundamental question of whether intracellular accumulation of zinc-chelating compounds is influenced by zinc content. Furthermore, application of this principle yielded a proof-of-concept method for β-cell-targeted drug delivery and bioactivity.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
TSQ, ≥98% (HPLC)
Sigma-Aldrich
GNF-4877, ≥98% (HPLC)