Zinc-Chelating Small Molecules Preferentially Accumulate and Function within Pancreatic β Cells
Zinc-Chelating Small Molecules Preferentially Accumulate and Function within Pancreatic β Cells
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DOI：
10.1016/j.chembiol.2018.10.019
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发表时间：
2019-02-21
影响因子：
8.6
通讯作者：
Annes, Justin P.
中科院分区：
文献类型：
--
作者：
Horton, Timothy M.;Allegretti, Paul A.;Annes, Justin P.
糖尿病是一种以胰腺β细胞功能障碍和耗竭为特征的高血糖病症。尽管存在用于监测体内β细胞功能的方法，但缺乏将治疗剂递送至β细胞的方法。我们利用β细胞浓缩锌的罕见能力，优先捕获β细胞内的锌结合分子，从而实现β细胞靶向化合物递送。我们确定，与外分泌胰腺相比，富锌β细胞和胰岛以锌依赖性方式优先积累TSQ（6-甲氧基-8-对甲苯磺酰氨基-喹啉）。接下来，我们询问在β细胞复制诱导化合物上附加锌螯合部分是否足以赋予优先β细胞积累和活性。事实上，该杂合化合物以锌依赖性方式优先在啮齿动物和人类胰岛内积累，并增加了对β细胞的复制促进活性的选择性。这些数据解决了锌螯合化合物的细胞内积累是否受锌含量影响的根本问题。此外，该原理的应用产生了用于β细胞靶向药物递送和生物活性的概念验证方法。
Diabetes is a hyperglycemic condition characterized by pancreatic beta-cell dysfunction and depletion. Whereas methods for monitoring beta-cell function in vivo exist, methods to deliver therapeutics to beta cells are lacking. We leveraged the rare ability of beta cells to concentrate zinc to preferentially trap zinc-binding molecules within beta cells, resulting in beta-cell-targeted compound delivery. We determined that zinc-rich beta 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 beta-cell replication-inducing compound was sufficient to confer preferential beta-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 beta 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 beta-cell-targeted drug delivery and bioactivity.