Development of compounds for multiple regulation of intracellular signaling

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Many diseases are known to be caused by the disorder of intracellular signaling machinery. The disorder would be repaired by developing an appropriate means of manipulating the signaling system. Thus, we attempted to develop man-made molecules to keep well-balanced intracellular signaling environment related to acquired immune deficiency syndrome (AIDS).Expression of HIV-1 provirus is governed primarily by cellular transcription factors NFκB, HIV-EP1, and Sp1. Inhibition of the function of these transcriptional proteins would lead to the interference of the replication of AIDS virus. Herein we report our approach for the inhibition of NFκB, HIV-EP1, and Sp1.The function of zinc finger protein could be inhibited if we could obtain metal chelators that target the zinc site of these transcription factors. We designed imidazole-pyridine-imidazole systems and found that compounds are efficient zinc chelators exhibiting remarkable inhibitory effect on the DNA binding of HIV-EP1 and Sp1 at 300 μM concentration. We further designed sulfurcontaining ligands, cysteamine-pyridine-cysteamine system, and found those to be uniformly effective at 30 μM concentration against both HIV-EP1 and Sp1.. We have also serendipitously shown that some of imidazole-pyridine-imidazole compounds inhiited the DNA binding of NFκB at 300 μM concentration. Further, it was shown that aurine tricarboxylic acid is a potent inhibitor of NFκB-DNA bindinf effective at 30 μM concentration.