2023 Fiscal Year Final Research Report
Structure and nuclease resistance mechanism of non-natural DNA aptamer drugs that inhibit blood coagulation function
| Project/Area Number |
21K12123
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 62010:Life, health and medical informatics-related
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| Research Institution | The University of Electro-Communications |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
瀧 真清 電気通信大学, 大学院情報理工学研究科, 教授 (70362952)
山越 智健 電気通信大学, レーザー新世代研究センター, 研究員 (30801245)
宮下 尚之 近畿大学, 生物理工学部, 准教授 (20452162)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | DNA Aptamer / DNA Covalent Aptamer / TBDcA / Combinatorial Screening |
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| Outline of Final Research Achievements |
TBA is a DNA aptamer (single-stranded DNA) that binds to thrombin and acts as an anticoagulant. It has the advantages of high specificity, non-immunogenicity, and the ability to have its drug effect nullified by its complementary strand.
The challenge is that they are easily degraded by nucleases present in serum. We performed MD calculations to investigate the stability of non-natural TBAs generated by replacing some natural DNAs with non-natural ones. Moreover, TBA modified with SO2F molecules (TBDcA) was synthesized experimentally and covalently bound to thrombin. TBDcA was found to be nuclease-resistant and its binding strength was enhanced by covalent binding while maintaining the drug effect.
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| Free Research Field |
原子・分子・光物理学
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| Academic Significance and Societal Importance of the Research Achievements |
TBAを始めとする核酸（DNA・RNA）アプタマーはSELEX法によって進化論的に作製され、標的分子に対する高い特異性を獲得するだけでなく、抗薬物抗体が生じ難く、相補鎖によって容易に中和でき安全である。薬剤としては極めて魅力的な性質を持っていると言える。本研究のTBDcAを例とする共有結合型修飾は、核酸アプタマーの弱点であるヌクレアーゼによる分解・排出を克服できると考えられる。今後応用領域を拡大する上で有望であり、社会的意義は高い。また、結晶化の困難な核酸アプタマーの構造の理解に向けたfoldingおよびunfoldingに関する動力学の理解は学術面での新展開にも繋がると期待される。
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