2024 Fiscal Year Final Research Report
A Multifaceted Drug Discovery Approach Targeting HBV HBx: Toward the Elimination of cccDNA"
| Project/Area Number |
22K07980
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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 53010:Gastroenterology-related
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| Research Institution | University of Yamanashi |
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Principal Investigator |
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| Project Period (FY) |
2022-04-01 – 2025-03-31
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| Keywords | HBV / HBｘ / 新規抗HBV薬開発 |
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| Outline of Final Research Achievements |
In this study, we targeted three HBx-mediated processes involved in HBV replication 1) transcriptional regulation, 2) protein degradation, 3) cccDNA regulation with the aim of developing lead compounds capable of eliminating HBV cccDNA. We identified four compounds that suppress HBV transcription and confirmed their anti-HBV activity in vitro. Furthermore, one compound showed antiviral efficacy in a humanized liver chimeric mouse model.We also identified that berberine, a component of antidiarrheal agents, enhances K48-linked polyubiquitination of HNF4α, a key regulator of HBV transcription, promoting its proteasome-dependent degradation and thereby suppressing HBV replication.
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| Free Research Field |
ウイルス学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、HBV cccDNAを排除する化合物創製を目標に研究を行ってきた。その結果、HBV転写制御を抑制する4種の化合物を見出した。これらの化合物は、in vitroの系で抗HBV活性が確認出来た。更に、このうちの1種は、ヒト肝細胞キメラマウスにおいて抗HBV活性が確認出来た。また、止瀉薬成分のBeberineが、HBVの転写制御に関与しているHNF4αのK48ポリユビキチン化を促進し、プロテアソーム依存的なタンパク分解を促進し、HBVの増殖を抑制する事を見出した。このような研究成果から、新たな作用機序の抗HBV薬開発に繋がる事が期待出来ると思われる。
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