Signaling basis of GPCR-acting drugs and their therapeutic mechanisms

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08264
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Tohoku University
• Principal Investigator: Inoue Asuka 東北大学, 薬学研究科, 准教授 (50525813)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: GPCR / Gタンパク質共役型受容体 / バイアスリガンド

Outline of Final Research Achievements

G-protein-coupled receptors (GPCRs) represent the largest class of human membrane proteins. They are also regarded as important targets for drug development. GPCRs mediate signal information from external stimuli such as hormones and drugs to intracellular responses. Characterizing signal profiling of GPCRs is critical for understanding not only GPCR biology, but also GPCR-targeting drugs. In this project, we developed various methods to assess G-protein-coupling profiles of GPCRs and characterized more than 100 GPCR signaling. Through bioinformatics analysis, this experimental database enabled us to develop an algorithm to score signaling profile based on a given GPCR sequence. These achievement will contribute to development of GPCR-targeting drugs including a signal-biased ligand, which is expected to serve as a safe drug with a reduced side effect.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究を通じてGPCRがどのような分子機構を介して特定の細胞内情報（シグナル）伝達を誘導するかを解析し、分子レベルでの知見を深めた。本研究では特に、バイアスリガンドと呼ばれる特定のシグナルを選択的に作動することのできるGPCR作用薬の解析に注力し、バイアスリガンドとGPCRの結合の構造基盤を解析するとともに、バイアスリガンドと結合したGPCRがどのような分子と相互作用することでシグナル伝達が生じるかについて、その作用機序の一端を解明した。この成果を利用して、副作用のない安全な薬としてのバイアスリガンドのさらなる研究が望まれる。