Drug discovery for Familial amyloid polyneuropathy (FAP), an incurable hereditary disease

2015 Fiscal Year Final Research Report

• Project/Area Number: 25253012
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Kumamoto University
• Principal Investigator: KAI HIROFUMI 熊本大学, 大学院生命科学研究部, 教授 (30194658)
• Co-Investigator(Kenkyū-buntansha): SHUTO Tsuyoshi 熊本大学, 大学院生命科学研究部(薬学系), 准教授 (80333524) ; SUICO Mary Ann Soten 熊本大学, 大学院生命科学研究部(薬学系), 助教 (20363525)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 化合物ライブラリースクリーニング / 家族性アミロイドポリニューロパチー

Outline of Final Research Achievements

Familial amyloid polyneuropathy (FAP) is one of the hereditary amyloidoses caused by a point mutation in the human plasma protein, transthyretin (TTR). Amyloid fibrils derived from TTR variants accumulate in peripheral nerves and visceral organs, leading to inflammation-associated failure of multiple organs. TTR variants are easily dissociated from tetramer to monomer, which is the first step to amyloidosis, due to the low energetic stability of TTR variant tetrameric structure in comparison with wild-type (WT) TTR. We aimed to determine novel drugs that could either stabilize extracellular TTR tetramer or inhibit TTR secretion from the cells by high-throughput screening (HTS). Here, Western blotting- and Thioflavin-based biochemical assays identified thirteen compounds that stabilize the TTR tetramer as well as two TTR amyloid-solubilizing agents, and one inhibitor of TTR secretion from the cells were identified in this study.

Free Research Field

薬理学