2012 Fiscal Year Final Research Report
Development of non-invasive drug delivery system using claudin modulator
| Project/Area Number |
21689006
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| Research Category |
Grant-in-Aid for Young Scientists (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
Medical pharmacy
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| Research Institution | Osaka University |
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Principal Investigator |
KONDOH Masuo 大阪大学, 薬学研究科(研究院), 准教授 (50309697)
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| Project Period (FY) |
2009 – 2012
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| Keywords | Claudin / 非侵襲性投与 / 細胞間隙 |
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| Research Abstract |
Claudins (CL) are a family of tetra-transmembrane proteins that are the structural and functional components of tight junctions (TJ). CLs are promising targets for drug development because of their role in mucosal drug absorption and carcinogenesis. However, CL-targeted drug development has been delayed because CLs have low antigenicity and preparing CL proteins is difficult. We developed a novel CL binder by using the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) and a baculoviral display system. After screening CL binders from a C-CPE mutant-displaying library by using CL-displaying budded baculovirus (BV) we isolated a C-CPE mutant called m19, which bound to CL1, CL2, CL4 and CL5. A 3-dimensional analysis showed that m19 has a structural backbone similar to C-CPE. The charge density of the CL-binding domains of m19 and C-CPE differed, suggesting that electrostatic interactions may occur between m19 and CLs. Treatment of epithelial cells with m19 decreased the paracellular but not transcellular integrity, and m19 enhanced jejunal absorption. This is the first report of the isolation of a CL binder with broad specificity. These findings will contribute to future preparation of CL binders for CL-targeted drug development.
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[Journal Article] Creation and biochemical analysis of a broad-specific claudin binder.2012
Author(s)
Takahashi, A.; Saito, Y.; Kondoh, M.; Matsushita, K.; Krug, S. M.; Suzuki, H.; Tsujino, H.; Li, X.; Aoyama, H.; Matsuhisa, K.; Uno, T.; Fromm, M.; Tamakubo, T.; Yagi, K.
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Journal Title
Biomaterials
Volume: 33
Pages: 3464-3474
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[Presentation] A simple screening system for claudin binders using an scFv library derived from claudin-immunized mice.2011
Author(s)
Miki Kodaka, Azusa Takahashi, Toshiaki Yamaura, Yohei Kakamu, Koji Matsuhisa, Kyohei Matsushita, Akihiro Watari, Masuo Kondoh, Kiyohito Yagi
Organizer
Experimental Biology 2011
Place of Presentation
Washington, DC, USA
Year and Date
20110404-13
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