喹啉类药临床应用广泛，但药物引起的神经炎、视网膜损伤等副作用，机理不明晰。我们前期应用化学遗传学方法研究发现：对硫胺素(VB1)转运子竞争性抑制是含喹啉环衍生物发挥生物学活性的一个普遍规律。但与副作用是否相关？项目拟从细胞、分子和在体三个层次开展：首先，研究氯碘喹啉(CQ)处理细胞效应，检测对细胞内硫胺素稳态及其参与生理功能的影响，阐明CQ拮抗VB1细胞机制，检测CQ衍生物机制保守性。其次，研究CQ拮抗VB1生化分子机制，计算机模建分析结合表面等离子共振等检测化合物与靶蛋白离体拮抗结合能力、构效关系及关键结构域；分子遗传分析响应等位基因对CQ及其衍生药物细胞敏感性遗传贡献，阐明CQ拮抗VB1分子基础。最后，通过食物及食物联合CQ诱导建立TD(VB1缺乏)动物模型，进一步研究喹啉在体对VB1代谢的影响及副作用消除策略。结果将拓展喹啉类活性机制认识，为联合用药预防副作用有重要的临床意义。

Quinoline derivatives are widely used in medicine. However, they cause various side effects such as neuritis, retinal damadge etc. The molecular mechanism remains obscure. Our previous studies have shown that quinoline derivatives inhibit the growth of yeast（S. cerevisiae）by specifically targeting thaimine transporters. Is this mode of action correlated with their side effects? In this project, the cellular mechanism of clioquinol (CQ) will be firstly sutdied by determination of effects of CQ on thaimine status and related.physiological metabolism in animal cells. Next, interaction sites, functional motifs and binding capacity between CQ and targeting proteins (thaimine related THI7p、SLC19A etc.) will be investigated by using computer modeling analysis combining with Surface Plasmon Resonance (SPR) technique, and sentivive genes to CQ associated with thaimine metabolism will be analyzed using functional variomics and genetic screening techniques as well. Additionally, thiamine deficiency (TD) animal model will be set up to study the effect of CQ on thiamine metabolism, the correlation between CQ and TD phenotype, and possible approaches of its side effects attenuation in vivo. These results will be confirmed by other quinoline derivatives. The work is expected to explain the medicinal molecular mechanism of quinoline derivatives,and provide significant therapeutic strategy for the side-effect attenuation of quinoline derivatives. It is meaningful to combine quinoline derivatives with vitamines to treat some diseases in the future.