Development of cationic histone deacetylase inhibitors as enhancer of gene transfection and expression

开发阳离子组蛋白脱乙酰酶抑制剂作为基因转染和表达的增强剂

• 批准号: 21590131
• 负责人: NAGAOKA Yasuo
• 金额: $ 2.91万
• 依托单位: Kansai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21590131/
• 关键词: リポフェクション; ヒストン脱アセチル化酵素阻害剤; 非ウイルスベクター; 遺伝子発現; HDAC; 遺伝子導入; HDAC阻害剤; ヒストン脱アセチル化酵素

Lipofection is the most versatile transfection methods to transfect genes into mammalian cells, because of its safety and its handiness. However, the expression efficiency of the transfected genes with this method is much lower than that with viral vector. We therefore attempted to develop highly efficient enhancer for lipofection. According to this objective, we accomplished the development of lipofection enhancers which enhance the expression of genes up to 23 times more than that of control. Structure of the enhancer is based on histone deacetylase(HDAC) inhibitors, which increase acetylation level of histone in nucleus resulting in the enhancement of transcription efficiencies. HDAC inhibitors also inhibit a cytosolic isozyme of HDAC_s, HDAC6, to facilitate transportation of transfected genes to the nucleus. This may also contribute to the enhancement of the transfected gene expression.

脂肪转染是将基因转染到哺乳动物细胞的最通用的转染方法，因为它的安全性和方便性。然而，用这种方法转染基因的表达效率远低于用病毒载体。因此，我们试图开发一种高效的增脂剂。根据这一目标，我们完成了脂肪感染增强剂的开发，其基因表达的增强程度是对照组的23倍。增强子的结构是基于组蛋白去乙酰化酶（HDAC）抑制剂，它增加细胞核中组蛋白的乙酰化水平，从而提高转录效率。HDAC抑制剂还抑制HDAC_s的胞质同工酶HDAC6，以促进转染的基因运输到细胞核。这也可能有助于增强转染基因的表达。

项目成果

Anti-tumor activity of new orally bioavailable 2-amino-5-(thiophen-2-yl) benzamide-series histone deacetylase inhibitors, possessing an aqueous soluble functional group as a surface recognition domain

• DOI: 10.1016/j.bmcl.2012.01.053
• 发表时间: 2012-03-01
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• 影响因子: 2.7
• 作者: Hirata, Yoshiyuki;Hirata, Masahiko;Uesato, Shinichi
• 通讯作者: Uesato, Shinichi

ヒストン脱アセチル化酵素阻害剤とその誘導体のリポフェクションに及ぼす影響

组蛋白脱乙酰酶抑制剂及其衍生物对脂转染的影响

• 发表时间: 2012
• 作者: 長岡康夫;吉野宏美;小林真理子;置田裕子;中野宏樹;上里新一
• 通讯作者: 上里新一

New microtubule polymerization inhibitors comprising a nitrooxymethylphenyl group

包含硝基氧基甲基苯基的新型微管聚合抑制剂

• DOI: 10.1016/j.bmc.2011.05.031
• 发表时间: 2011
• 期刊: Bioorg.Med.Chem.
• 作者: Y.Kawaratani;T.Harada;Y.Hirata;Y.Nagaoka;S.Uesato;他5名
• 通讯作者: 他5名

Molecular bases of cyclodextrin adapter interactions with engineered protein nanopores

• DOI: 10.1073/pnas.0914229107
• 发表时间: 2010-05-04
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Banerjee, Arijit;Mikhailova, Ellina;Bayley, Hagan
• 通讯作者: Bayley, Hagan

Antitumor effect of liposomal histone deacetylase inhibitor-lipid conjugates in vitro.

• DOI: 10.1248/cpb.59.1386
• 发表时间: 2011-11
• 期刊: Chemical & pharmaceutical bulletin
• 影响因子: 1.7
• 作者: Y. Hattori;Y. Nagaoka;Manami Kubo;H. Yamasaku;Y. Ishii;Hiroko Okita;Hiroki Nakano;S. Uesato;Y. Maitani