Novel zinc chelators with dual activity in the inhibition of the kappa B site-binding proteins HIV-EP1 and NF-kappa B.
Both HIV-EP1 (also called PRDII-BF1 or MBP-1), a zinc finger protein, and NF-kappa B, a Rel family protein, bind to kappa B site present in the enhancer of multiple cellular and viral genes involved in immune function and inflammatory response including HIV-1 LTR and human interferon beta gene. When cells are exposed to extracellular stimuli such as virus or phorbol ester, the activity of both HIV-EP1 and NF-kappa B is induced. Thus, kappa B site-directed transcription could be regulated by two distinct proteins in a cooperative way. Novel heterocyclic compounds comprising (dimethylamino)pyridine and histidine units, i.e., 1-4, have been designed and synthesized, aiming at inhibition of these kappa B site-binding proteins to discriminate their functions. These compounds exhibited remarkable zinc-binding capability as revealed by NMR study. Compounds 1 and 2 showed a marked inhibitory effect on the DNA binding activity of HIV-EP1 by removing zinc without interfering with the DNA binding activity of NF-kappa B. Since it has been demonstrated that zinc somehow influences the DNA binding of NF-kappa B, the effect of these heterocyclic compounds and their zinc complexes on NF-kappa B was examined. Zinc complexes of 3 and 4 exhibited the inhibitory effect on the DNA binding of NF-kappa B and/or homodimeric complexes of p50 and p65 subunits of NF-kappa B without affecting HIV-EP1. Thus, it became possible to inhibit either one of the two kappa B site-binding proteins without inhibiting the other.(ABSTRACT TRUNCATED AT 250 WORDS)
Otsuka
M
M
Institute for Chemical Research, Kyoto University, Japan.
Fujita
M
M
Aoki
T
T
Ishii
S
S
Sugiura
Y
Y
Yamamoto
T
T
Inoue
J
J
D001483:Base Sequence; D001665:Binding Sites; D002614:Chelating Agents / Q000737:chemistry*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D014157:Transcription Factors; D015032:Zinc / Q000737:chemistry*; D016335:Zinc Fingers
D002614:Chelating Agents; D004268:DNA-Binding Proteins; C063232:HIVEP1 protein, human; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D014157:Transcription Factors; D004247:DNA; D015032:Zinc