2022 Fiscal Year Final Research Report
Elucidation of the mechanism of action of bacterial non-coding RNAs and its application for new drug discovery
| Project/Area Number |
20K21281
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 38:Agricultural chemistry and related fields
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Project Period (FY) |
2020-07-30 – 2023-03-31
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| Keywords | 非コードRNA / リボスイッチ / 遺伝子の発現調節 / 細菌 / PreQ1 / tRNA / RNA合成 |
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| Outline of Final Research Achievements |
In this study, I synthesized derivatives based on the chemical structure of the parent compound with dibenzofuran ring. Then, I evaluated the transcription termination activities of these derivatives by in vitro transcription assay using RNA polymerase. The resulting transcription termination activities of two of these new compounds were increased compared with the parent compound. The crystal structures of PreQ1 riboswitch in complex with these two compounds were determined by molecular replacement method. The structures revealed that the derivatives bound to the PreQ1 binding site of the riboswitch. In the crystal structures, the derivatives were stabilized by the stacking interactions with the conserved nucleobases of PreQ1 riboswitch. In addition, the structure revealed that the derivatives form specific hydrogen bonds with the nucleobases of PreQ1 riboswitch.
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| Free Research Field |
応用生物化学
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| Academic Significance and Societal Importance of the Research Achievements |
感染症に対する医薬品は低分子医薬が主流であるが、多剤耐性菌が出現し問題となっている。この克服には新規な抗生剤の開発が不可欠である。本研究では、細菌RNAを標的とした新規薬剤の創製を目指して実験を実施した。対象としたRNAは細菌に特有のPreQ1リボスイッチであり、PreQ1の生合成に関わる遺伝子の発現をPreQ1濃度に応じて調節する。PreQ1はtRNAのアンチコドン1字目に存在する修飾ヌクレオシドの一つであるキューオシンの前駆体であり、正確なタンパク質の合成に重要である。従って、PreQ1リボスイッチと結合する合成化合物を取得すれば、RNAを標的とした新規抗生剤の開発に繋がると考えられる。
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