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

本研究的最终目标是开发治疗转甲状腺素(TTR)-家族性淀粉样变性多发性神经病（FAP）的药物。我们之前发现，抑制内质网中TTR四聚体化，从而阻断突变TTR的分泌，可能是治疗FAP的候选药物的靶点。在这项研究中，我们对TTR四聚化抑制剂进行了计算机虚拟筛选。在250万种化合物中，我们选择了大约20种化合物，研究了所选化合物对突变体TTR分泌和四聚化的影响。最后，我们发现了两种化合物可以减少突变体TTR的分泌，其中一种可以抑制突变体TTR的四聚化。此外，为了对化学文库进行高通量筛选，我们开发了一种基于荧光的检测系统，用于体外监测TTR四聚体化，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.