Establishment of artificial ligands technology for peptide hormone receptors with functional mutations

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08544
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Kanazawa University
• Principal Investigator: Sakai Kastuya 金沢大学, がん進展制御研究所, 助教 (10523318)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 受容体 / リガンド / 環状ペプチド

Outline of Final Research Achievements

Artificial ligands for growth factor receptors are clinically applicable. We here tried identification of artificial ligands for insulin receptor (IR) using macrocyclic peptide screening, and characterized MET-agonist macrocyclic peptides to establish artificial ligand technology based on macrocyclic peptide. Expression and purification of IR protein with its kinase activity was difficult. Now, purification of IR in nanodiscs is being investigated. We have proved that 1) artificial ligands based on macrocyclic peptide are able to have similar activity compared to natural ligands, 2) partial agonists based on macrocyclic peptide are able to induced biased or selective cellular responses compared to natural ligands, and 3) macrocyclic peptides interact with thier target protein in an unique manner. These results illustrate potential of artificial ligands based on macrocyclic peptides.

Free Research Field

バイオテクノロジー

Academic Significance and Societal Importance of the Research Achievements

ペプチド・タンパク質ホルモンや/増殖因子は細胞膜受容体を介して生理活性を発揮する。本課題により低分子人工ペプチド性リガンドを着実に創製できる技術を実証したこと、これらの技術の基盤となる知見を得られたことは、医薬品として際立った薬効をもつ複数の低分子生理活性医薬を創製する技術原理を確立することにつながる。