Project/Area Number |
21K05302
|
Research Category |
Grant-in-Aid for Scientific Research (C)
|
Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
|
Research Institution | Tokyo Institute of Technology (2023) Institute of Physical and Chemical Research (2021-2022) |
Principal Investigator |
CHANG Tsung-che 東京工業大学, 物質理工学院, 特任助教 (00774853)
|
Project Period (FY) |
2021-04-01 – 2024-03-31
|
Project Status |
Completed (Fiscal Year 2023)
|
Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
|
Keywords | Prodrug / Sialyltransferases / In vivo synthesis / Acrolein / Sialyltransferase / Gold metal / Immunotherapy / Metal catalysis / Sialic acid / Glycoalbumin |
Outline of Research at the Start |
Cancer is the second leading cause of death globally, and is responsible for about 10 million deaths per year. The research could innovate the cancer immunotherapy to achieve efficiently cancer therapy for life extension and reduce numbers and death number.
|
Outline of Final Research Achievements |
Abnormal glycosylation is a hallmark of cancer, and hypersialylation increases tumor metastasis by promoting immune evasion and inducing tumor cell invasion and migration. Inhibiting sialylation is thus a potential anticancer treatment strategy. However, targeting sialic acids is difficult because of the lack of selective delivery tools. Here, we present a prodrug strategy for selectively releasing the global inhibitor of sialylation peracetylated 3Fax-Neu5Ac (PFN) in cancer cells using the reaction between phenyl azide and endogenous acrolein, which is overproduced in most cancer cells. The prodrug significantly suppressed tumor growth in mice as effectively as PFN without causing kidney dysfunction, which is associated with PFN. The use of sialylated glycans as immune checkpoints is gaining increasing attention, and the proposed method for precisely targeting aberrant sialylation provides a novel avenue for expanding current cancer treatments.
|
Academic Significance and Societal Importance of the Research Achievements |
本研究では、アクロレインが多く存在するがん細胞内でシアル酸転移酵素阻害剤を合成し、がん細胞上のみで糖鎖構造を合成化学的に変化させ、副作用なくマウスのがんを治療することに成功しました。がん細胞内で薬剤を合成するという本研究の戦略は、他の作用機序を有する抗がん剤の開発においても、副作用を減らす戦略としての活用が期待されます。
|