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

本研究的最终目的是开发治疗甲状腺素运载蛋白（TTR）-家族性淀粉样多发性神经病（FAP）的药物。我们先前确定，抑制内质网中的TTR四聚化，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，我们进行了计算机虚拟筛选TTR四聚体的抑制剂。在250万种化合物中，我们选择了约20种化合物，并检查了所选化合物对突变体TTR的分泌和四聚化的影响。最后，我们鉴定了2种减少突变TTR分泌的化合物，其中一种抑制突变TTR的四聚化。此外，进行高通量筛选的化学库，我们开发了一个基于荧光的测定系统，监测TTR四聚体在体外，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.