2022 Fiscal Year Final Research Report
Development of powerful ad exhaustive inhibitors for ribosome-inactivating proteins
| Project/Area Number |
19K05699
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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 37010:Bio-related chemistry
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| Research Institution | Toho University |
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Principal Investigator |
Saito Ryota 東邦大学, 理学部, 教授 (90327974)
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| Co-Investigator(Kenkyū-buntansha) |
後藤 勝 東邦大学, 理学部, 准教授 (80379289)
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Keywords | pterin-7-carboxamide / リシン毒素A鎖阻害剤 / X線結晶構造解析 |
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| Outline of Final Research Achievements |
In the present study, we discovered that pterin-7-carboxamides with aromatic L-amino acid pendants interacted with the active site of RTA in a 2-to-1 mode, where one inhibitor molecule bound to the primary pocket and the second one entered the secondary pocket in the active site of RTA. We also found that pterin-7-carboxamide with GlyPheLys(Z) pendant interacts with the two pockets in the active site of RTA simultaneously to exhibit good RTA inhibitory activity. X-ray crystallographic analysis of inhibitor/RTA complexes revealed that the conformational changes of Tyr80 and Asn122 as well as an interaction with Asn78 in RTA were critical for triggering the entry of inhibitor molecules into the secondary pocket of the RTA active site.
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| Free Research Field |
生物有機化学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、リシン毒素A鎖(RTA)活性部位中の２つのポケットを同時に塞ぐ有機小分子阻害剤を初めて開発した。さらに、２つのポケットを塞ぐために必要な阻害剤ならびにタンパク質の構造情報も明らかにした。これらの化合物が高いRTA阻害活性を示したことから、これまで未解明であった学術的な問い「高RTA阻害活性化合物の開発に必要不可欠な構造情報」に対して世界で初めて明確な解答を出すことができた。されに、本研究の成果によって、RTA阻害剤の開発が飛躍的に発展するだけでなく、RTAと同じ作用機序で毒性を発現する毒素タンパク質が関わるすべての中毒の治療薬開発の飛躍的な発展に繋がると考えられる。
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