Synthetic inhibitors of regulatory proteins involved in the signaling pathway of the replication of human immunodeficiency virus 1.
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.
Otsuka
M
M
Institute for Chemical Research, Kyoto University, Japan.
Fujita
M
M
Sugiura
Y
Y
Yamamoto
T
T
Inoue
J
J
Maekawa
T
T
Ishii
S
S
D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
D011725:Pyridines; D014157:Transcription Factors