Drug discovery research using cyclic dinucleotide derivatives with peptide structures as bioisosteres

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K16333
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Tsuji Genichiro 国立医薬品食品衛生研究所, 有機化学部, 主任研究官 (90786196)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 環状ジヌクレオチド / c-di-GMP / バイオフィルム / STING / アミン / ケミカルバイオロジー

Outline of Final Research Achievements

Cyclic dinucleotides (CDNs) are molecules with a variety of biological activities. In this study, CDN derivatives based on amine molecules have synthesized and evaluated their functions. The introduction of an amine skeleton into the CDN molecule enabled the synthesis of a wide variety of derivatives and can impart functions such as improved resistance to degradative enzymes. Although the activity was not sufficient, the synthesized derivatives showed biofilm formation inhibitory activity against Gram-positive bacteria, and stimulation or inhibition of STING, an immune-related protein in mammals.

Free Research Field

ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

CDNは病原菌のバイオフィルム形成阻害作用やI型インターフェロンの誘導作用など、医薬品としての利用が期待されている。本研究では、アミン構造を利用したCDN誘導体によって、迅速な合成、分解酵素への耐性、また膜透過性の改善など、医薬品として重要な機能の付与が可能であることを示した。この成果は、将来のCDNの医薬品としての応用において有用な知見となると期待される。