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1.
Bioorg Med Chem Lett ; 29(16): 2162-2167, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31272791

RESUMO

Zinc fingers have rarely been regarded as drug targets. On the contrary, the zinc-binding site of enzymes has often been considered a target of inhibitors. We previously developed a dithiol compound called SN-1 that binds to the zinc finger protein tumor necrosis factor receptor-associated factor 6 (TRAF6) and suppresses downstream nuclear factor-κB (NF-κB) signaling. To determine the minimal structure requirements of TRAF6 inhibitors based on SN-1, NF-κB inhibitory activity and cytotoxicity of its derivatives including new compounds were examined. SN-2, an oxidative type of prodrug of SN-1 with 2-nitrophenylthio groups via disulfide, has the minimum structure for an inhibitor of TRAF6, as seen with cellular experiments. The importance of two side chains with a thiol group was shown with molecular modelling. This study may lead to development of selective TRAF6 inhibitors in the near future.


Assuntos
Fator 6 Associado a Receptor de TNF/antagonistas & inibidores , Dedos de Zinco/genética , Humanos , Estrutura Molecular
2.
Chem Biol Drug Des ; 99(4): 573-584, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34882966

RESUMO

Various chimeric receptors have been developed and used for biological experiments. In the present study, we constructed three types of chimeric receptor activator of nuclear factor-kappa B (RANK) with the glutathione S-transferase (GST) protein in the extracellular domain, and stimulated them using newly synthesized chemical trimerizers with three glutathiones. Although this stimulation did not activate these proteins, we unexpectedly found that the chimera named RANK-GST-SC, in which GST replaced a major part of the RANK extracellular domain, activated nuclear factor-kappa B (NF-κB) signaling approximately sixfold more strongly than wild-type RANK without the ligand. The dimerization of extracellular GST is considered to function as a switch outside the cell, and signal transduction then occurs. GST has been widely employed as a tag for protein purification; GST-fusion protein can be conveniently captured by glutathione-conjugated beads and easily purified from impurity. The present study is a pioneering example of the novel utility of GST and provides information for the development of new chemical biology systems.


Assuntos
NF-kappa B , Ligante RANK , Quimera/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Osteoclastos/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo
3.
Chem Pharm Bull (Tokyo) ; 59(12): 1555-8, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22130380

RESUMO

Nuclear factor-κB (NF-κB) is an inducible transcription factor activated by a variety of cytokines, and promotes the transcription of genes involved in cancer, inflammation, autoimmune disease, and viral infection, among others. Because of its involvement in numerous disease processes, considerable research has focused on NF-κB as a potential drug target. We previously reported that cupric ion (Cu(2+)) blocks NF-κB activation. However, Cu(2+) is unsuitable for drug applications. The copper complex of an artificial peptide HPH-Pep (HPH-Pep-Cu(2+)) was a promising alternative, but it did not easily cross the cell membrane. We report the development of a NF-κB inhibiting Cu(2+) complex with improved cell-penetrating activity arising from the coupling of a Tat peptide to HPH-Pep-Cu(2+).


Assuntos
Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacologia , Cobre/química , Cobre/farmacologia , Histamina/análogos & derivados , NF-kappa B/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Células HeLa , Histamina/química , Histamina/farmacologia , Humanos , NF-kappa B/imunologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/química , Produtos do Gene tat do Vírus da Imunodeficiência Humana/farmacologia
4.
ChemMedChem ; 12(23): 1935-1941, 2017 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-28884970

RESUMO

Despite various inhibitors targeting the zinc center(s) of enzymes, drugs that target zinc fingers have not been examined in detail. We previously developed a dithiol compound named SN-1 that has an inhibitory effect on the function of zinc finger transcription factors, but its mechanism of action has not yet been elucidated. To establish a general principle for new drugs, the details of the action of SN-1 against a zinc finger protein were examined. As a zinc-finger-containing protein, we focused on TRAF6, which is related to cancer and inflammation. Binding of SN-1 to TRAF6 and its effect on TRAF6 ubiquitination were examined in vitro, and the binding mode was calculated by computational methodology. Furthermore, ubiquitination of TRAF6 and downstream signaling was examined by cell-based experiments. The results show that SN-1 binds to TRAF6, inhibiting its auto-ubiquitination and downstream NF-κB signaling. Docking studies indicate that SN-1 binds directly to the first zinc finger of TRAF6. This binding disrupts the neighboring structure, that is, the RING finger domain, to suppress the ubiquitin ligase activity of TRAF6. Taken together, this study provides a platform for developing new small molecules that target zinc finger proteins.


Assuntos
Fator 6 Associado a Receptor de TNF/antagonistas & inibidores , Tolueno/análogos & derivados , Sítios de Ligação/efeitos dos fármacos , Células Cultivadas , Células HEK293 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Simulação de Acoplamento Molecular , Estrutura Molecular , Fator 6 Associado a Receptor de TNF/química , Fator 6 Associado a Receptor de TNF/metabolismo , Tolueno/química , Tolueno/farmacologia , Ubiquitinação/efeitos dos fármacos
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