Improvement of the PDK4 inhibitors based on the tertiary structure analysis and application for the treatment of heart failure

2015 Fiscal Year Final Research Report

• Project/Area Number: 15K15312
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Jichi Medical University
• Principal Investigator: Nagai Ryozo 自治医科大学, 医学部, 学長 (60207975)
• Co-Investigator(Kenkyū-buntansha): YOKOYAMA Shigeyuki 理化学研究所, 横山構造生物学研究室, 上席研究員 (00159229) ; AIZAWA Kenichi 自治医科大学, 医学部, 准教授 (70436484) ; NAKAYA Takeo 自治医科大学, 医学部, 講師 (80512277)
• Project Period (FY): 2015-04-01 – 2016-03-31
• Keywords: PDK4 / 心不全 / 癌 / 立体構造解析 / in silico解析

Outline of Final Research Achievements

It is important to improve the PDK4 inhibitors on the basis of X-ray crystallographic analyses of the PDK4 inhibitors bound to the PDK4 protein. We successfully prepared, by the cell-free protein synthesis method, a large amount of the PDK4 protein sample suitable for crystallization. We developed a novel method to form a PDK4 protein covalently bonded with an inhibitor by introducing an unnatural amino acid designed for click chemistry in a specified position of the PDK4 protein. Furthermore, using a heart failure model mouse, we showed that two kinds of new PDK4 inhibitors were useful for the treatment of heart failure.

Free Research Field

循環器内科学