The analysis of HIV transcriptional regulation and development of new HIV drugs

2023 Fiscal Year Final Research Report

• Project/Area Number: 17K08638
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Nagoya City University
• Principal Investigator: Asamitsu Kaori 名古屋市立大学, 医薬学総合研究院(医学), 講師 (20381783)
• Co-Investigator(Kenkyū-buntansha): 岡本 尚 名古屋市立大学, 医薬学総合研究院(医学), 名誉教授 (40146600)
• Project Period (FY): 2017-04-01 – 2024-03-31
• Keywords: HIV / 転写 / P-TEFｂ

Outline of Final Research Achievements

Antiretroviral therapy for human immunodeficiency virus (HIV) has advanced to the point where combinations of anti-HIV drugs have shown considerable therapeutic efficacy. However, there is still the problem of activation from latently infected viruses to be overcome, along with the side effects of drugs and the problem of controlling drug-resistant viruses. One of the best targets is the HIV transcriptional activation process, which is mainly regulated by the host transcription factor NFκB and the virus-derived transcriptional activator Tat. In this project, we analyzed these factors. In particular, we focused on Tat-mediated HIV transcriptional activation and found a novel HIV inhibitor candidate that targets CDK9, a component of P-TEFb, which forms a complex with Tat during transcriptional activation. Further studies are needed to develop anti-HIV drugs.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

Tatによる転写活性化は、Tatが宿主の転写伸長因子P-TEFbと複合体を形成することで開始される。本研究課題では、Tat特異的に形成されるCDK9上のファーマコフォアCDK9 hidden cavityを用いたin silicoスクリーニングから、CDK9活性を阻害する化合物を同定した。本知見の学術的意義として、CDK9阻害剤の有用なファーマフォアを提供できたことがあげられる。また、HIV転写過程は特に潜伏感染状態を制御する重要な過程にも関わらず、それを標的としたHIV治療薬は現在開発されていない。これを克服する手段を提供できたことが、社会的意義としてあげられる。