Otsuka M, Fujita M, Sugiura Y, Yamamoto T, Inoue J, Maekawa T, Ishii S
Institute for Chemical Research, Kyoto University, Japan.
Bioorg Med Chem. 1997 Jan;5(1):205-15. doi: 10.1016/s0968-0896(96)00203-9.
NF-kappa B, HIV-EP1, Sp1, and E1A are transcriptional proteins involved in the long terminal repeat-directed expression of HIV-1. The inhibitory effect of 18 dimethylaminopyridine-based compounds against these regulatory proteins was studied. Experiments using NF-kappa B-beads showed that histidine-pyridine-histidine compounds and their zinc complexes are inhibitory not only for the NF-kappa B-DNA binding, but also for the binding of NF-kappa B with the inhibitory protein I kappa B. Discriminative inhibition of the DNA binding of two distinct C2H2 type zinc finger proteins HIV-EP1 and Sp1 was also attempted using the synthetic compounds. Whereas some compounds inhibited the DNA binding of both HIV-EP1 and Sp1 at 300 microM, others preferentially and completely inhibited HIV-EP1 without much suppression of Sp1. Mercapto compounds were more potent and uniformly inhibitory against both HIV-EP1 and Sp1 at 30 microM. Disulfide compounds were also remarkably inhibitory against HIV-EP1 and Sp1 also at 30 microM whereas the shorter-chain disulfides 7 and 9 were effective only for HIV-EP1. S-Alkyl derivatives preferentially inhibited HIV-EP1 at 300 microM. The dimethylamino compound was the sole compound inhibitory only against Sp1, being non-inhibitory against HIV-EP1. Relevant combinations of these inhibitors would allow us to inhibit NF-kappa B, HIV-EP1, and Sp1 in any combinations. Inhibition of the TBP binding of C4 type zinc finger protein adenovirus E1A was also examined. It was found that two compounds induced, at 50 mM concentration, effective inhibition of the TBP binding of E1A, demonstrating that it is possible in principle to inhibit the protein-protein interaction of zinc finger proteins.
核因子-κB、HIV-EP1、Sp1和E1A是参与HIV-1长末端重复序列定向表达的转录蛋白。研究了18种基于二甲基氨基吡啶的化合物对这些调节蛋白的抑制作用。使用核因子-κB磁珠进行的实验表明，组氨酸-吡啶-组氨酸化合物及其锌配合物不仅对核因子-κB与DNA的结合有抑制作用，而且对核因子-κB与抑制蛋白IκB的结合也有抑制作用。还尝试使用合成化合物对两种不同的C2H2型锌指蛋白HIV-EP1和Sp1的DNA结合进行区分抑制。虽然一些化合物在300微摩尔浓度下抑制了HIV-EP1和Sp1与DNA的结合，但其他化合物优先且完全抑制了HIV-EP1，而对Sp1的抑制作用不大。巯基化合物在30微摩尔浓度下对HIV-EP1和Sp1的抑制作用更强且更均匀。二硫化合物在30微摩尔浓度下对HIV-EP1和Sp1也有显著抑制作用，而较短链的二硫化合物7和9仅对HIV-EP1有效。S-烷基衍生物在300微摩尔浓度下优先抑制HIV-EP1。二甲基氨基化合物是唯一仅对Sp1有抑制作用而对HIV-EP1无抑制作用的化合物。这些抑制剂的相关组合将使我们能够以任何组合抑制核因子-κB、HIV-EP1和Sp1。还研究了C4型锌指蛋白腺病毒E1A与TBP的结合抑制情况。发现两种化合物在50毫摩尔浓度下可有效抑制E1A与TBP的结合，表明原则上有可能抑制锌指蛋白的蛋白质-蛋白质相互作用。
