Synthetic study of functional mismatch binding molecules for selective hydrolysis of expanded repeat RNAs

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K14516
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Bio-related chemistry
• Research Institution: Osaka University
• Principal Investigator: YAMADA Takeshi 大阪大学, 産業科学研究所, 助教 (80633263)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: DNA / トリヌクレオチドリピート / 低分子 / ミスマッチ塩基対

Outline of Final Research Achievements

To develop small molecules that selectively hydrolyze repeat RNAs that cause neurodegenerative diseases, various NCD derivatives, comprised from NCD moiety and various nucleophilic functional groups, were synthesized. Then the effects of these derivatives on the hydrolysis of mismatch RNAs were analyzed by RP-HPLC and MALDI-TOF-MASS. Although those results confirmed that the C-C mismatch site in the RNA duplex was prone to be hydrolyzed in the presence of compounds, selective hydrolysis of the CGG repeat RNA were not observed. However, it was clarified NCD-SH and NCD-CC modified with thiol groups rapidly dimerize on CGG repeats and bind tightly to their targets, and NCD-IMI, a derivative of NCD modified with imidazole groups, can efficiently place metal complexes on DNA. Those derivatives were published in three different theses in peer-reviewed journal.

Free Research Field

生物有機化学

Academic Significance and Societal Importance of the Research Achievements

遺伝子中のトリヌクレオチドリピートの異常伸長は脆弱X症候群・ハンチントン病など、多くの神経変成疾患の原因となるが、発症・重症化のメカニズムは不明な部分が多い。本研究の成果であるNCD-SHやNCD-CCは、脆弱X症候群の原因であるCGGリピートDNAと強固に結合するため、脆弱X症候群を解明するための分子プローブとしての利用が期待できる。また、DNA中のCGG/CGG特異的に結合して二重鎖DNA上に金属錯体を配置することができるNCD-IMIは、DNAオリガミなどのDNAナノテクノロジーへの応用が期待できる。