Synthesis of selenol-bearing membrane-bound antioxidative enzyme and its rescue effect from cell death due to the GPx-4 knockdown

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K06617
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
• Research Institution: Sojo University
• Principal Investigator: HARATAKE Mamoru 崇城大学, 薬学部, 教授 (40325668)
• Co-Investigator(Kenkyū-buntansha): 中村 秀明 崇城大学, 薬学部, 講師 (30435151)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: セレノール / グルタチオンペルオキシダーゼ / セレン / 抗酸化酵素

Outline of Final Research Achievements

To obtain an effective glutathione peroxidase-4 (GPx-4) mimic under the physiological conditions, a lipid bilayer membrane-compatible selenenylsulfide derivative, 1-oxo-headecyl-seleno-L-cysteine-methyl-Se-yl-S-L-penicillamine methyl ester (OHSeP), was synthesized. The GPx-like catalytic activity of OHSeP in phosphatidylcholine (PC)-based colloidal liposomes was evaluated by the NADPH method using hydrogen peroxide as a substrate in physiological aqueous media. The OHSeP/PC liposomes preferably exerted in a GPx-like catalytic activity. A knockdown of the GPx-4 expression is lethal, since GPx-4 plays critical roles as a component of the antioxidant cell defense system. When siRNA-induced GPx-4 knockdown HepG2 cells were treated with the OHSeP/PC liposomes, the catalytic activity of OHSeP could successfully rescue from the cell death.

Free Research Field

衛生薬学

Academic Significance and Societal Importance of the Research Achievements

ヒトは進化の過程において，呼吸によって不可避に生じる過酸化物を消去するためにセレン原子を利用する強力な還元能を獲得している。しかし，セレン原子の特性は未だ医薬品へは応用されていない。本研究で得られた成果は，セレン原子の比類なき特性を活かした医薬品開発を進めるための基礎的知見となると考えられる。