Development of drugs targeting secretory inhibition of transthyretin for familial amyloidotic polyneuropathy

这项研究的最终目标是开发治疗转甲状腺素(TTR)-家族性淀粉样多发性神经病(FAP)的药物。我们以前发现，抑制内质网中的TTR四聚化，从而阻断突变的TTR四聚体的分泌，可能是治疗FAP的候选药物的靶点。在本研究中，我们进行了TTR四聚体抑制剂的电子计算机虚拟筛选。从250万个化合物中筛选出约20个化合物，考察了这些化合物对突变体TTR分泌和四聚化的影响。最后，我们鉴定了两个减少突变TTR四聚体分泌的化合物，其中一个化合物抑制突变TTR四聚化。此外，为了进行高通量的化学文库筛选，我们开发了一个基于荧光的检测系统，用于监测体外TTR四聚体，并计划在未来的研究中使用该系统。

The final goal of this study is to develop drug for treatment of Transthyretin (TTR)-Familial Amyloidotic Polyneuropathy (FAP). We previously identified that inhibition of TTR tetramerization in the endoplasmic reticulum that blocks secretion of mutant TTR could be a target of candidate drug for treatment of FAP. In this study, we performed in silico virtual screening of inhibitor for TTR tetramerization. Among 2.5 million compound, we selected about 20 compounds and examined the effect of selected compounds on secretion and tetramerization of mutant TTR. Finally, we identified 2 compounds that reduce secretion of mutant TTR, one of which inhibits tetramerization of mutant TTR. Moreover, to perform high-throughput screening of chemical libraries, we developed a fluorescence-based assay system that monitor TTR tetramerization in vitro and plan to use this system in future study.