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

艾滋病前病毒启动子区域的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-EP1和Sp1蛋白与这些序列特异性结合，参与艾滋病病毒AMF的转录复制。本研究针对蛋白质和核酸，即抑制这些转录蛋白的功能并设计针对长末端重复序列Sp1和HIV-EP1的DNA裂解剂，是一种在DNA识别结合部位含有锌的锌指蛋白。我们制备了各种基于吡啶的锌络合剂，通过提取锌来灭活这些蛋白。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络合剂。特别是，一种含萘基的化合物对锌蛋白表现出了良好的抑制活性。我们针对HIV前病毒DNA序列的特异性识别进行了新型多肽核酸的分子设计。我们以D-天冬氨酸和L-天冬氨酸为起始基团，制备了具有光学活性的单体成分和相应的含甘氨酰-b-丙氨酸骨架的肽核酸低聚物。因此，本研究的结果包括成功地设计了新型金属螯合剂，抑制了锌蛋白的功能，并开发了一种新型的靶向艾滋病前病毒基因的肽核酸。

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.