硫氧还蛋白还原酶（TrxR）是细胞内氧化还原调控体系的核心成员之一，对维持细胞的氧化还原平衡起着重要作用。TrxR功能的失调与多种疾病的发生关系密切，因而利用外源性物质来调控TrxR的活性可能会成为治疗或者预防相关疾病的新策略。多种证据表明，在神经退行性疾病中，TrxR的活性显著降低。在此我们提出发展模拟TrxR功能的小分子，期待此种分子能够借助细胞内丰富的谷胱甘肽来实现对氧化型硫氧还蛋白的还原，进而发挥神经保护的功效。此外，这类分子还可作为探针，把细胞内两条主要的、但少有交叉的氧化还原调节体系（即硫氧还蛋白系统和谷胱甘肽系统）衔接起来，为更好地认识这两个体系的的生理功能提供工具。我们将首先构筑一个小分子化合物库，对经筛选发现的先导化合物在分子水平和细胞水平进行评价，希望能够首次发现TrxR的小分子模拟物，并在此基础上进一步考察该类分子的生物学功效。

Thioredoxin reductase (TrxR) plays important roles in regulating cellular redox homeostasis, and the abnormal functions of TrxR have been linked to a number of diseases. Thus, employing exogenous agents to manipulate the enzyme’s function could be a novel strategy to treat such diseases. In the case of neurodegeneration, a significant impairment of the TrxR activity has been observed. We proposed herein to develop novel glutathione-dependent small molecules to mimic the physiological functions of TrxR, and expect these TrxR mimetics are potential therapeutic agents for neurodegenerative diseases. Furthermore, the GSH-dependent TrxR mimetics will also bridge the thioredoxin system and the glutathione system, two major cellular redox regulating systems yet with few crosstalks. We will construct a small library containing diverse disulfides, diselenides and molecules with -S-Se- bond. After screening, the leads will be evalulated in molecular and cellular levels. We expect to discover, for the first time, small molecule mimetics of TrxR, and the biological functions of these TrxR mimetics will be explored.