NES保有蛋白の核外移行阻害を標的とする新規医薬リード化合物の探索

寻找靶向抑制 NES 蛋白核输出的新型药物先导化合物

• 批准号: 13672213
• 负责人: MURAKAMI Nobutoshi
• 金额: $ 2.3万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672213/
• 关键词: nuclear export signal; CRM1; Rev protein; MAPKK; antttumors agent; anti-HIV; valtrate; callystatin A; 抗がん剤; 核外移行シグナル; 核外移行阻害活性; 1'-acetoxylchavicol acetate; 抗癌剤

Recently, some proteins with nuclear export signal (NES), which is a characteristic sequence of amino acids, were shown to be exported from nucleus to cytoplasm with the aid of NES receptor protein CRM1. Mitogenactivated protein kinase kinase (MAPKK) and Rev were shown to be representative NES possessing proteins and play important roles in cytoplasm after export from nucleus. The former is concerned with proliferation of various tumor cells, the latter is required by replication of HIV 1 virus. In addition, inhibition of NES receptor, CRM1, led to suppress both proliferation of the tumor cells and replication of HIV1 virus potently. Up to date, leptomycin B (2) and callystatin A (3) have been only clarified to be inhibitors of CRM1. In this context, we constructed an assay system to search for another NES inhibitor by using the NLS GFP NES transformed yeast and disclosed a new NES inhibitor, vartrate (1), from Valerianae Radix through bioassayguided separation. By using the biotinylated probe derived from callystatin A (3), varflate (1) was presumed to inhibit export of the NES possessing proteins through binding to the Cys 529 in CRM1 in the same fashion as 2 and 3. Furtherriiore, the binding site of 1 to CRM1 was elucidated to be an epoxy moiety from the reactant of 1 and N acetylcysteine methyl ester

最近，一些具有核输出信号（内斯）的蛋白质被证明可以借助内斯受体蛋白CRM 1从细胞核输出到细胞质中，所述核输出信号是氨基酸的特征序列。丝裂原活化蛋白激酶激酶（Mitogenactivated protein kinase kinase kinase，MAPKK）和Rev是典型的具有蛋白质的内斯，从细胞核输出后在细胞质中发挥重要作用。前者与各种肿瘤细胞的增殖有关，后者是HIV 1病毒复制所必需的。此外，抑制内斯受体CRM 1，导致有效地抑制肿瘤细胞的增殖和HIV 1病毒的复制。到目前为止，只澄清了来普霉素B（2）和callystatin A（3）是CRM 1的抑制剂。在此背景下，我们构建了一个检测系统，以寻找另一个内斯抑制剂，通过使用NLS GFP内斯转化酵母，并公开了一个新的内斯抑制剂，通过生物测定引导分离从缬草根中。通过使用来自callystatin A的生物素化探针（3），推测varflate（1）通过与CRM 1中的Cys 529结合以与2和3相同的方式抑制具有内斯的蛋白质的输出。此外，1与CRM 1的结合位点被阐明为来自1与N乙酰半胱氨酸甲酯的反应物的环氧部分

项目成果

N.Murakami et al.: "Synthesis of stable analogs in blood and conformational analysis of arenastatin A, a potent cytotoxic spongean depsipeptide"Tetrahedron. 57(19). 4323-4336 (2001)

N.Murakami 等人：“血液中稳定类似物的合成和阿那他汀 A（一种有效的细胞毒性海绵缩酚肽）的构象分析”四面体。

N,Murakami: "New Semi-synthetic Quassinoids with Leading in Vivo Anti-malarial Activity"J. Med. Chem. 46(4). 638-641 (2003)

N，Murakami：“具有领先体内抗疟疾活性的新型半合成Quassinoids”J。

N,Murakami: "Exploration for anti-cancer leads through synthetic approach utilizing biologi cally active natural products as seed principles"Natural Medicines. 56(3). 73-77 (2002)

N,Murakami：“通过利用具有生物活性的天然产物作为种子原理的合成方法来探索抗癌”天然药物。

N.Murakami et al.: "Total synthesis of agosterol A, an MDR-modulator from a marine sponge"Chem. Eur. j.. 7(12). 2663-2670 (2001)

N.Murakami 等人：“来自海绵的 MDR 调节剂阿戈甾醇 A 的全合成”Chem.

N.Murakami et al.: "New Rev-Transport Inhibitor with Anti-HIV Activity from Valerianae Radix"Bioorg. &Med. Chem. Lett.. 12(20). 2807-2810 (2002)

N.Murakami 等人：“缬草中具有抗 HIV 活性的新型 Rev 转运抑制剂”Bioorg。