Pharmacologic stimulation of insulin granule acidification increases β-cell zinc content and augments β-cell-targeted drug delivery.

ABSTRACT: Pathologic loss of insulin-producing pancreatic β-cells is a hallmark of diabetes that is potentially reversible through regenerative therapy. However, existing replication-promoting compounds lack β-cell specificity, limiting their clinical application. To overcome this challenge, we generated βRepZnC, a zinc-chelating replication compound designed to leverage the uniquely high zinc content of β-cells for targeted delivery. Herein, we identify pharmacological agents that boost β-cell zinc and improve the targeted delivery and bioactivity of βRepZnC. Using a high-content, image-based screen with the zinc fluorophore TSQ, we identified GR-46611 as a pharmacologic enhancer of β-cell zinc levels. Time-lapse TSQ imaging revealed that GR-46611 rapidly elevated intracellular zinc, prompting furt

SUBMITTER: Lee S 

PROVIDER: S-EPMC12494549 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature