2019 Fiscal Year Final Research Report
Development of Halogen-Containing Compounds Potent against Wild-type and Multidrug-Resistant HIV-1 Strains
Project/Area Number |
17H04222
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Infectious disease medicine
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Research Institution | National Center for Global Health and Medicine |
Principal Investigator |
Hiroaki Mitsuya 国立研究開発法人国立国際医療研究センター, その他部局等, 研究所長 (20136724)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Keywords | HIV-1 / 阻害剤開発 / ハロゲン結合 |
Outline of Final Research Achievements |
In general, fluorination increases lipophilicity because the carbon-fluorine bond is more hydrophobic than the carbon-hydrogen bond, often enhancing cell membrane penetration and oral bioavailability of the compounds. Here, we newly designed and synthesized various novel PIs and attempted to determine proper fluorination sites in various moieties consisting of certain PIs. We found that various PIs acquire more potent anti-HIV-1 activity with proper fluorination. An existing challenge in development of novel PIs is that presently clinically available PIs are metabolized by cytochrome P450 enzymes and require co-administration of CYP inhibitors, causing annoying drug-drug interactions leading to adverse effects. We found that alkylamino modification at C5-position of tetrahydropyrano-tetrahydrofuran-containing PIs potentiates activity against multi-PI-resistant HIV-1 and the stability to CYP enzymes.
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Free Research Field |
感染症内科学、血液内科学
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Academic Significance and Societal Importance of the Research Achievements |
本成果は、近年問題となっているHIV関連神経認知障害(HAND)の治療だけでなく、変遷しつつある抗レトロウイルス療法(Anti-retroviral therapy;ART)に対応した抗HIV薬開発の発展に資する。ARTの発展により感染者の余命が伸長しHANDが問題視されるようになった。中枢神経系透過性の高い2個のフッ素原子を有する新規化合物の開発に成功した。現在臨床試験が実施されているEFdAやカボテグラビルに代表されるようにARTは1日1回から1週間、1ヶ月に1回の投薬への変遷過程にある。今後は、ARTの発展と共に生じる新たな課題に応じた創薬開発が必要とされる。
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