| 研究課題/領域番号 |
18K14347
|
|---|
| 研究機関 | 国立研究開発法人理化学研究所 |
|---|
研究代表者 |
VONG KENWARD 国立研究開発法人理化学研究所, 開拓研究本部, 基礎科学特別研究員 (50775369)
|
|---|
| 研究期間 (年度) |
2018-04-01 – 2020-03-31
|
| キーワード | biocompatibility / artificial metalloenzyme / enzymes / gold-catalyzed reaction / drug release |
|---|
| 研究実績の概要 |
In order to realize the goal of developing a prodrug therapy based on glycosylated artificial metalloenzymes (GArM), two areas are actively being investigated:
1. Development of gold-catalyzed, drug release reactions: For this project, doxorubicin and endoxifen prodrug derivatives were synthesized. Their gold-mediated release under aqueous conditions was confirmed for in vitro studies. Cytotoxicity assays using a number of different cancer cell lines were also run showing promising cytotoxic activity.
2. Development of artificial metalloenzymes: For a paper focused on the development of albumin-based artificial metalloenzymes, several contributions were made. Performed studies related to in vitro reactivity with several different substrates. Performed binding experiments to obtain stoichiometric data in relation to metalloenzyme formation, as well as to determine substrate affinities. Molecular modeling studies were also carried out to validate a mechanism. Using umbelliprenin prodrug derivatives in the presence artificial metalloenzymes, cytotoxicity assays were done using a number of different cancer cell lines to highlight its cytotoxic activity. This paper has been finalized and is in the process of revision.
|
| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
Besides progress made on the main project of developing gold-catalyzed drug release reactions, significant contributions were made for the completion of two papers (one was published while another is currently under revision). The published paper is in regards to determining the mechanism of gold-catalyzed, propargyl ester based protein labeling. It was found that this likely acts through a rare example of C(sp2)-C(sp) aryl-alkynyl cross coupling via spontaneous reductive elimination. This work was performed with a PhD student under supervision of the awardee and has now come to completion.
In another publication, the awardee contributed significantly to the development of albumin-based artificial metalloenzymes. Working as a team, experiments were done to not only highlight the ability of the albumin protein scaffold to confer biocompatibility to bound metal catalysts, but also to show the working framework for an anticancer prodrug therapy based on activation via ruthenium-catalyzed cross coupling. This work has been completed and is in the process of final revisions.
|
| 今後の研究の推進方策 |
Stemming from the work related to artificial metalloenzymes, the awardee is in the process of developing albumin mutants containing unnatural amino acids. The aim is to create artificial metalloenzymes where metal catalysts are covalently linked to the protein. This should confer a greater degree of biocompatibility to these protein-metal catalysts. Using this work, the awardee will then apply it for in vivo drug release using the developed gold-catalyzed, drug release reactions.
|
