Development of a highly visual, simple, and rapid test for the discovery of novel insulin mimetics in living vertebrates.

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2013
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Abstract
Diabetes mellitus is a global epidemic with major impacts on human health and society. Drug discovery for diabetes can be facilitated by the development of a rapid, vertebrate-based screen for identifying new insulin mimetic compounds. Our study describes the first development of a zebrafish-based system based on direct monitoring of glucose flux and validated for identifying novel anti-diabetic drugs. Our system utilizes a fluorescent-tagged glucose probe in an experimentally convenient 96-well plate format. To validate our new system, we identified compounds that can induce glucose uptake via activity-guided fractionation of the inner shell from the Japanese Chestnut (Castanea crenata). The best performing compound, UP3.2, was identified as fraxidin and validated as a novel insulin mimetic using a mammalian adipocyte system. Additional screening using sets of saponin- and triazine-based compounds was undertaken to further validate this assay, which led to the discovery of triazine PP-II-A03 as a novel insulin mimetic. Moreover, we demonstrate that our zebrafish-based system allows concomitant toxicological analysis of anti-diabetic drug candidates. Thus, we have developed a rapid and inexpensive vertebrate model that can enhance diabetes drug discovery by preselecting hits from chemical library screens, before testing in relatively expensive rodent assays.
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lee2013developmentacs Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Lee, Jinho;Jung, Da-Woon;Kim, Woong-Hee;Um, Jung-In;Yim, Soon-Ho;Oh, Won Keun;Williams, Darren R;
Journal ACS chemical biology
Year 2013
DOI
10.1021/cb4000162
URL
Keywords Keywords not found

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