Metal-chelating inhibitors of a zinc finger protein HIV-EP1. Remarkable potentiation of inhibitory activity by introduction of SH groups.
HIV-EP1 is a C2H2 type zinc finger protein which binds to DNA kappa B site present in the long terminal repeat of HIV provirus. Previously we have reported zinc chelators having histidine--pyridine--histidine skeleton and were successful in inhibiting the DNA binding of HIV-EP1 by removing zinc from the zinc finger domain. Aiming at the potentiation of the inhibitory activity of our previous zinc chelators, herein synthesized were novel chelators comprising pyridine and aminoalkanethiol. These showed marked inhibitory activity on the DNA binding of HIV-EP1. In particular, one of them having a bis(2-mercaptoethyl) amino side chain showed inhibitory activity (IC50, approximately 4 microM) 10 times stronger than that of the strongest inhibitor that we reported previously. It appeared that these inhibited the DNA binding of HIV-EP1 by a mechanism distinct from that of the previous histidine-based inhibitors.
Fujita
M
M
Institute for Chemical Research, Kyoto University, Japan.
Otsuka
M
M
Sugiura
Y
Y
D000818:Animals; D001483:Base Sequence; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry*; 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; D013438:Sulfhydryl Compounds; D014157:Transcription Factors; D004247:DNA; D015032:Zinc