随着阿尔茨海默症（AD）发病机制研究的深入，人们认识到β-淀粉样蛋白（Aβ）在AD的发生发展中起着关键作用。但是，通过直接抑制Aβ生成或聚集的抗AD药物研发并未获得理想效果。因此，探索抑制Aβ生成新机制，发现新型抗AD药物具有重要意义。最新研究发现，α-分泌酶ADAM-10 mRNA的5'非编码区的富G-序列能够形成G-四链体结构。若拆散该G-四链体，将上调该酶的表达，有效减少Aβ的生成。申请人在多年从事Aβ和G-四链体化学生物学研究基础上，筛选出三个能拆散mRNA 5'UTR G-四链体的小分子配体。本项目将在此基础上，构建针对这一新机制的药物评价体系；设计、合成并筛选出新型具有拆散ADAM-10 mRNA G-四链体和抑制Aβ生成的小分子化合物；深入研究化合物通过上调α-分泌酶表达，实现抑制Aβ生成的分子机制；为建立全新的治疗策略和发展新型抗AD治疗药物提供理论基础和先导化合物。

Amyloid beta protein (Aβ) has a key role for the development of Alzheimei's disease (AD) along with gradually increased understanding of nosogenesis study of AD. Current research and development of drugs inhibiting the formation and aggregation of Aβ have been failing to achieve ideal results. So, research on anti-AD drugs based on new mechanism of inhibiting the formation of Aβ is very important. According to the latest achievements, unfolding the mRNA 5'UTR G-quadruplex of α-secretase ADAM10 would up-regulate the expression of this enzyme, further significantly decrease the formation of Aβ. According to our results of years of work on the chemical biology of Aβ and G-quadruplex and using the compounds library and acitivity screening system created by our lab, three small molecular compounds have been identified to be able to unfold the mRNA G-quadruplex. In this research, on the basis of the latest research results, we will design, synthesize and identify some new small molecules that could unfold the ADAM10 mRNA 5'UTR G-quadruplex and inhibite the formation of Aβ, and futher study the molecular mechanism of the up-regulation of α-secretase to inhibit the formation Aβ. This project might provide a more solid theoretical and experimental basis and new lead compounds for the establishment of new therapy strategy and the development of new anti-AD drugs.