Development of Sulfo-Sialic Acids into Next-Generation Antimicrobial Agents
| Project/Area Number |
18K06577
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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 47010:Pharmaceutical chemistry and drug development sciences-related
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| Research Institution | Kobe University |
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Principal Investigator |
ヴァヴリッカ クリストファー 神戸大学, 科学技術イノベーション研究科, 准教授 (20809199)
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| Co-Investigator(Kenkyū-buntansha) |
清田 洋正 岡山大学, 環境生命科学研究科, 教授 (30234397)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Granted (Fiscal Year 2019)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
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| Keywords | Bioproduction / Anti-virals / Sialic acid / Synthetic biology / Sulfonic acids / Fluorine / Neuraminidase / Covalent inhibitors / Microwave reaction / Decarboxylation / Fluoro sugars / Influenza neuraminidase / Drug development / Novel carbohydrates / Covalent inhibitor / Sulfo-sialic acid |
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| Outline of Annual Research Achievements |
To speed up production of the medicinal chemistry targets, microbial systems to bioproduce target compounds were developed. Concepts for designing, building, testing and improving bioproduction systems were proven using alkaloid targets in a model study. The model alkaloid pathway is similar to our proposed sialic acid derivative synthesis in that decarboxylation is a key step, and also regarding key aldehyde intermediates. Therefore new aldehyde containing routes to the proposed sialic acid derivatives were explored using successful model reactions. Finally, a microbial system for 9-O-acetyl-sialic acid bioproduction was constructed. 9-O-acetylsialic acid is a potential probe or inhibitor of coronavirus, as well as a key intermediate of our proposed sialic acid derivatives.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
Regarding the original plan to produce fluorinated sialic acid derivatives as inhibitors of influenza, we have made progress in the introduction of fluroine into the C-1 position of open-chain analogs of our proposed compounds. In one model reaction, fluoromethy phenyl sulfone could undergo addition to a model aldehyde. In addition, we have made great progress in the development of next-generation methods for the production of valuable medicinal compounds. These synthetic biology methods for carrying out related reactions have already resulted in several high impact publications. Therefore we are confident that these new processes will continue to produce valuable targets relating to the proposed study.
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| Strategy for Future Research Activity |
We will continue to focus on two approaches to further develop our proposed fluorinated sialic acid analogs:
1) Production of open-chain analogs of fluorinated sialic acids. This will include an 8 carbon aldonic acid derived from oxidation of sialic acid. The open-chain analogs will be tested as inhibitors of influenza neuraminidase. Re-cyclization of the open-chain analogs may also be tested.
2) Microbial bioproduction of key intermediates using aldolase and O-acetyltransferase enzymes. Improvement of enzyme sequences will be carried out using protein structure modeling. In vivo production of target compounds will be tested in Escherichia coli. Comparison of the metabolism of fluorine labeled compounds vs natural compounds will be investigated.
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Report
(2 results)
Research Products
(8 results)
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[Journal Article] "Mechanism-based Tuning of Insect 3,4-Dihydroxyphenylacetaldehyde Synthase for Synthetic Bioproduction of Benzylisoquinoline Alkaloids "2019
Author(s)
Christopher J. Vavricka, Takanobu Yoshida, Yuki Kuriya, Shunsuke Takahashi, Teppei Ogawa, Fumie Ono, Kazuko Agari, Hiromasa Kiyota, Jianyong Li, Jun Ishii, Kenji Tsuge, Hiromichi Minami, Michihiro Araki, Tomohisa Hasunuma, Akihiko Kondo
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Journal Title
Nature Communications
Volume: 10
Pages: 2015-2015
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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