2007 Fiscal Year Final Research Report Summary
Combinatorial library of asymmetric metal complexes and lead discovery for protein surface recognition
| Project/Area Number |
18510185
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Living organism molecular science
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| Research Institution | Osaka University |
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Principal Investigator |
OHKANDA Junko Osaka University, ISIR, Associate Professor (50233052)
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| Co-Investigator(Kenkyū-buntansha) |
KATO Nobuo Osaka University, ISIR, Professor (50150537)
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| Project Period (FY) |
2006 – 2007
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| Keywords | trisbipvridine metal complexes / protein surface reel / module assembly / molecular glue / chymotrypsin / thrombin / inhibition mode / mix-library |
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| Research Abstract |
Modulation of protein-protein interactions by small organic agents still remains a difficult challenge due to the large interfacial areas of buried surface involved in such interactions. The goal of this project is to construct a stable assembly of low-molecular-weight modules that consist of appropriate functional groups for complementary binding to the targeting protein surfaces. A series of trisbipyridne ruthenium complexes consisting various functional group at 4, 4'-position of the bipyridine ligands was synthesized, and was screened for inhibition activity against alpha-chymotrypsin using the chromogenic substrate, which allows us to run the kinetic enzyme assay. Among them, the complex bearing phenylalanine residues showed the best inhibition activity (73% inhibition at 50 pM), whereas the one having cationic charged residue derived from lysines showed no activity, suggesting that the complementary electrostatic interaction in between the complex and the protein surface near the
… More
active site remarkably dictates the inhibition potency. For further test in this strategy to detect the protein structural information such as asymmetrical and chiral environment, we applied a dynamic combinatorial strategy using Fe (II), which can be a central metal with faster ligand exchanging rate, with the series of pyridine ligands prepared in this study. When 1:1 molar ratio of Glu-containing (bpyGlu) and Lys-containing (LysGlu) pyridines are mixed with iron(II) chloride, a mixture of four isomeric complexes is expected to yield in 1:3:3:1 ratio. When thrombin (pI=7) was treated with the mixture solution, the activity was suppressed more effectively than 100% of Fe(bpyGlu)3 or Fe(bpyLys)3, respectively. This result suggested that asymmetric complex, either Fe(bpyGlu) (bpyLys)2 or Fe(bpyGlu)2(bpyLys) possess higher inhibition activity than the corresponding symmetric complex. We believe that the metal complex library would provide a useful tool for the lead discovery for protein surface recognition, which should be more vulnerable with asymmetric inhibitors. Less
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[Journal Article] Module Assembly for Protein-Surface Recognition : Geranylgeranyltransferase I Bivalent Inhibitors for Simultaneous Targeting of Interior and Exterior Protein Surfaces2008
Author(s)
Shinnosuke, Machida, Kakeru, Usuba, Michelle, A., Blaskovich, Akiko, Yano, Kazuo, Harada, Said, M., Sebti, Nobuo, Kato, Junko, Ohkanda
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Journal Title
Chemistry -A European Journal 14
Pages: 1392-1401
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Farnesyltransferase and Geranylgeranyltransferase I inhibitors upregulate RhoBexpression by HDAC1 dissociation, HAT association and histone acetylation of the RhoBpromoter.2007
Author(s)
Frederic L. Delarue, Jalila Adnane, B. Joshi, Michelle A. Blaskovich, De-anWang, James Hawker, Frank Bizouarn, J. Ohkanda, Kuichun Zhu, Andrew D. Hamilton, Srikumar Chellappan, Said M. Sebti
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Journal Title
Oncogene 26
Pages: 633-640
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Famesyliransferase and Geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter2007
Author(s)
Frederic, L., Delarue, Jalila, Adnane, B., Joshi, Michelle, A., Blaskovich, De-an, Wang, James, Hawker, Frank, Bizouarn, Junko, Ohkanda, Kuichun, Zhu, Andrew, D., Hamilton, Srikumar, Chellappan, Said, M., Sebti
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Journal Title
Oncogene 26
Pages: 633-640
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Structure-Activity relationship study among fusicoccane deterpene glycosides on anti-cancer activity2008
Author(s)
Takatsugu, Inoue, Yuriko, Maruyama, Hajime, Nitta, Yoshio, Homma, Takeshi, Sassa, Junko, Ohkanda, Nobuo, Kato
Organizer
Chemical Society of Japan,88 National Meeting
Place of Presentation
Tokyo
Year and Date
2008-03-27
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Practical synthetic route to a differentiation-inducing fusicoccin derivative2008
Author(s)
Yusuke, Higuchi, Masamitsu, Hiraoka, Yuriko, Maruyama, Takatsugu, Inoue, Hajime, Nitta, Takeshi, Sassa, Junko, Ohkanda, Nobuo, Kato
Organizer
Chemical Society of Japan,88 National Meeting
Place of Presentation
Tokyo
Year and Date
2008-03-27
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Bivalent inhibitors of Type-I geranylgeranyltransferase for simultaneous recognition of interior and exterior protein surfaces2007
Author(s)
Junko, Ohkanda, Shinnosuke, Machida, Nobuo, Kato, Michelle, A., Blaskovich, Said, M., Sebti, Kazuo, Harada
Organizer
American Chemical Society 234th National Meeting
Place of Presentation
Boston, USA
Year and Date
20070819-23
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Differentiation-inducing Activity and Cytotoxicity of Fusicoccin Derivatives2007
Author(s)
Takatsugu, Inoue, Yusuke, Higuchi, Yuta, Fukai, Hajime, Nitta, Takashi, Kasube, Yoshio, Homma, Takeshi, Sassa, Junko, Ohkanda, Nobuo, Kato
Organizer
Chemical Society of Japan,87 National Meeting
Place of Presentation
Osaka
Year and Date
20070325-28
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Synthesis and evaluation of Auto inducer agonists2007
Author(s)
Masamitsu, Hiraoka, Yoshimi, Yano, Tomikazu, Kawano, Hidetada, Hirakawa, Asuka, Kobayashi, Takahiro, Hirata, Akhito, Yamaguchi, Junko, Ohkanda, Nobuo, Kato
Organizer
20th Internanoscience COE program
Place of Presentation
Osaka
Year and Date
2007-01-16
Description
「研究成果報告書概要(欧文)」より
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