Development of specific oxidative modification inhibitor for endoplasmic reticulum stress sensor

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K22498
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: Okayama University
• Principal Investigator: Uehara Takashi 岡山大学, 医歯薬学総合研究科, 教授 (00261321)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: 一酸化窒素 / 小胞体ストレス / UPR / ニトロシル化

Outline of Final Research Achievements

Nitric oxide (NO) regulates the enzymatic activity of IRE1α, a sensor molecule of UPR, through protein S-nitrosylation. Since NO resulted in apoptosis via inactivation of UPR, we consider a compound that specifically suppresses this oxidative modification without inhibiting endonuclease activity of IRE1α is effective. Certainly, there are many diseases dependent on UPR dysfunction such as Parkinson's disease or diabetes. Therefore, we attempted to isolate a specific oxidative modification inhibitor for the endoplasmic modification site. From in silico screening, we could isolate a candidate lead compound. In order to increase the pharmacological potency, two derivatives were also produced. We then confirmed their inhibitory effects that restored the blockage of the UPR pathway by NO in a concentration-dependent manner.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病や糖尿病の発症には小胞体ストレスが介在していることが明らかとなっている．一方で，一酸化窒素はセンサータンパク質であるIRE1に結合することで，本来は抗細胞死に関わる経路を遮断することでより脆弱にさせることを証明してきた．そこで，この経路を回復させるような化合物の作出は病態発症を軽減する可能性があると考えた．スクリーニングから有力な候補化合物を単離することに成功した．これらは酵素活性を阻害することなく，NOによる修飾のみを抑制することがわかった．今後，動物モデルに適用してその効力を検討することで，新規作用メカニズムを有した治療薬開発に有益な情報をもたらすと推定される．