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Molecular design of anti-AIDS drugs targeting the human transcription machinery employed for the replication of AIDS virus

针对艾滋病病毒复制所用的人类转录机制的抗艾滋病药物的分子设计

基本信息

批准号：
12557219
负责人：
OTSUKA Masami
金额：
$ 7.49万
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：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557219/
关键词：
artificial ligand AIDS virus NFkB HIV-EP1 Sp1 peptide nucleic acids HIV-EPl Spl

项目摘要

The Long Terminal Repeat, the promoter region of the AIDS provirus contains a tandem kB sequence, three consecutive GC boxes, and a TATA box. Proteins NFkB, HIV-EP1 and Sp1 specifically bind to these sequences and paticipate in the transcription amf replicatiom of AIDS virus. The present research aimed at proteins and nucleic acids, i. e., the inhibition of the functions of these transcriptional proteins and the design of DNA-cleaving agents targeting the Long Terminal RepeatSp1 and HIV-EP1 is a zinc finger proteins containing zinc in their DNA recognition-binding sites. We prepared various pyridine-based zinc chelators to inactivate these proteims by abstracting zinc. We synthesized biphenyl-type metal chelators with an aromatic substituent on the pyridine, considering the enzyme binding. In particular, a compound with a naphthyl group showed excellent inhibitory activity against a zinc protein.We carried out a molecular design of novel peptide nucleic acid for the specific recognition of the DNA sequence of HIV provirus. We prepared optically active monomer constituents and the corresponding oligomer of peptide nucleic acids containing a glycyl-b-alanine backbone starting with D-and L-aspartic acids.Thus, the results of the present research include the successful design of novel metal chelators that inhibit the function of zinc proteins and development of a novel peptide nucleic acid that could target the DNA of AIDS provirus.

艾滋病前病毒的启动子区长末端重复序列包含一个串联的kB序列、三个连续的GC盒和一个TATA盒。NFkB、HIV-EP 1和Sp1蛋白与这些序列特异性结合，参与AIDS病毒的转录和复制。目前的研究主要针对蛋白质和核酸，即蛋白质和核酸。例如，抑制这些转录蛋白的功能和设计靶向长末端重复序列Sp1和HIV-EP 1的DNA切割剂是在其DNA切割结合位点含有锌的锌指蛋白。我们制备了各种吡啶基锌螯合剂，通过提取锌来固定这些蛋白质。考虑到酶的结合作用，我们合成了吡啶上带有芳香取代基的联苯型金属螯合剂。特别地，具有萘基的化合物对锌蛋白表现出优异的抑制活性。我们进行了一种新的肽核酸的分子设计，用于特异性识别HIV前病毒的DNA序列。我们制备了以D-和L-天冬氨酸为起始原料的含有甘氨酰-b-丙氨酸骨架的肽核酸的光学活性单体组分和相应的寡聚体，因此，本研究的结果包括成功设计了抑制锌蛋白功能的新型金属螯合剂和开发了能够靶向AIDS前病毒DNA的新型肽核酸。