Molecular design of anti-AIDS drugs targeting the viral and host zinc proteins

针对病毒和宿主锌蛋白的抗艾滋病药物的分子设计

基本信息

批准号：
15390038
负责人：
OTSUKA Masami
金额：
$ 8.51万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390038/
关键词：
HIV zinc protein zinc complex NFκB ヒドロキサム酸ナフチル基

项目摘要

HIV RNA is reversetranscribed upon infection and subsequently integrated into the genome of the host cell. The provirus thus formed remains latent until certain stimuli activate the transcription of the integrated viral genes. Various viral and host proteins are involved in the transcription of viral genes and are regarded as significant, molecular targets for the treatment of AIDS.In the present study, we are interested in integrase, HFκB, HIV-EP1, Sp1 and HIV Tat. All of them are zinc proteins or that closely related to zinc.We have studied on the design and synthesis of zinc-binding artificial molecules containing a pyridine and two chelating side chains, aiming at the inhibition of the function of various zinc proteins. In 2003, we attempted the introduction of aromatic substituents onto the pyridine ring and examined hydroxamic acid in addition to cysteamine as the chelating side chains. We prepared pyridines bearing phenyl 2-tolyl, 3-tolyl, 4-tolyl, 3,5bis(trifluoromethyl)phenyl, 3,4-dimethoxyphenyl, 1-naphthyl,3-chlorophenyl substituents. A zinc chelator having 1-naphthyl group was found to be inhibitory against the farnesyltransferase, an important zinc protein in the signal transduction of Ras protein, with IC_<50> 1.9 μM. This compound induced morphological change in K-ras-NRK cells at.0.5 μg/ml and showed growth inhibition of K-ras-NRK cells with IC_<50> 0.32 μg/ml.In 2004, the inhibitory effect of polyphenol carboxylic acids, such as aurintricarboxylic acid, gallic acid, and coumarin derivatives on the DNA binding of NFκB were studied. Evans blue was also found to be inhibitory against the DNA binding of NFκB. Molecular modeling studies suggest an explanation for the inhibition.Thus, we are successful in the synthesis of novel compounds that inhibit function of zinc proteins related to AIDS.

HIV RNA 在感染后被逆转录，随后整合到宿主细胞的基因组中，从而形成的原病毒保持潜伏状态，直到某些刺激激活整合的病毒基因的转录，并参与病毒基因的转录。被认为是治疗艾滋病的重要分子靶点。在本研究中，我们感兴趣的是整合酶、HFκB、HIV-EP1、Sp1和HIV Tat，它们都是锌蛋白或与锌密切相关的蛋白。关于设计2003年，我们尝试在吡啶环上引入芳香族取代基，并研究了异羟肟酸。我们制备了带有苯基2-甲苯基、3-甲苯基、4-甲苯基的吡啶， 3,5 双（三氟甲基）苯基、3,4-二甲氧基苯基、1-萘基、3-氯苯基取代基具有 1-萘基的锌螯合剂被发现对法呢基转移酶具有抑制作用，法呢基转移酶是 Ras 信号转导中的重要锌蛋白。蛋白质，IC_50>1.9μM 该化合物诱导K-ras-NRK的形态变化。 0.5 μg/ml对K-ras-NRK细胞有生长抑制作用，IC_50>0.32 μg/ml。2004年，金精三酸、没食子酸、香豆素衍生物等多酚羧酸的抑制作用研究还发现伊文思蓝可抑制 NFκB 的 DNA 结合。因此，我们成功合成了抑制与艾滋病相关的锌蛋白功能的新型化合物。

项目成果

期刊论文数量（41）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

M.Abdel-Aziz: "Synthesis and Hybridization Property of Novel 2',5'-Iso-DNA Mimic Chiral Pentide Nucleic Acids"Bioorg.Med.Chem.Lett.. 13(6). 1041-1043 (2003)

M.Abdel-Aziz：“新型 2,5-Iso-DNA 模拟手性戊肽核酸的合成和杂交特性”Bioorg.Med.Chem.Lett.. 13(6)。

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

A molecular modeling study of inhibitors of nuclear factor kappa-B (p50) - DNA binding

DOI：
10.1023/b:jcam.0000021835.72265.63
发表时间：
2003-12-01
期刊：
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
影响因子：
3.5
作者：
Pande, V;Sharma, RK;Ramos, MJ
通讯作者：
Ramos, MJ

Inhibitory Activities Against Topoisomerase I & II by Polyhydroxybenzoyl Amide Derivatives and their Structure-Activity Relationship

对拓扑异构酶 I 的抑制活性

DOI：
发表时间：
2004
期刊：
Bioorg.Med.Chem.Lett. 14(7)
影响因子：
0
作者：
Sugimoto;Y.;Nakato;T.;Kita;A.;Takahshi;Y.;Hatae;N.;Tabata;H.;Tanaka;S.;Ichikawa;A;Hirouchi et al.;Mohamed Abdel-Aziz
通讯作者：
Mohamed Abdel-Aziz

H.Kurosaki: "Crystal Structure of 7,8-Dihydroxy-4-methylcoumarin"Anal.Sci.. 19. 647-648 (2003)

H.Kurosaki：“7,8-二羟基-4-甲基香豆素的晶体结构”Anal.Sci.. 19. 647-648 (2003)