2020 Fiscal Year Final Research Report
Development of chemcial modifications optimized for oligonucleotide-protein complex formation
| Project/Area Number |
17H04886
|
|---|
| Research Category |
Grant-in-Aid for Young Scientists (A)
|
| Allocation Type | Single-year Grants |
|---|
| Research Field |
Bio-related chemistry
|
|---|
| Research Institution | Tokyo Institute of Technology |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2017-04-01 – 2021-03-31
|
| Keywords | 核酸医薬 / 化学修飾核酸 / アンチセンス核酸 / RNaseH / オフターゲット効果 |
|---|
| Outline of Final Research Achievements |
We have proposed a methodology to suppress the off-target effects of RNaseH-dependent antisense oligonucleotides by introducing chemical modifications optimized for nucleic acid-protein complex formation. We performed molecular dynamic simulations to extract structural features upon the RNasaH/DNA/RNA complex. Based on the simulated structures, we designed and synthesized chemical modification that restricts the position of complex formation. We confirmed the position of RNaseH complex formation was restricted upon the incorporation of chemical modifications. In addition, transcriptome analysis showed that the number of off-target genes was suppressed and the cell survival rate was improved. These results will contribute to the development of safer antisense oligonucleotides.
|
| Free Research Field |
生体関連化学
|
| Academic Significance and Societal Importance of the Research Achievements |
核酸医薬品は、従来は治療することのできなかった疾患に対し、治療法を開発することができる新たな医薬品の形態です。非常に効果的な方法論である一方、予期せぬ標的外遺伝子の作用は安全性上の懸念となり、核酸医薬品の迅速な開発を妨げてきました。本研究では核酸医薬品の安全性上の懸念の解決を目指し、核酸医薬品の一種であるRNaseH依存型アンチセンス核酸において、原理的に安全性が向上する方法論を提唱しました。本成果は、核酸医薬品の今後の迅速な開発に貢献することが期待されます。
|
