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A new drug to enhance tight junctions

  • Graduate School of Pharmaceutical Sciences
  • Department of Basic Medicinal Sciences
  • Laboratory of Structural Molecular Pharmacology
  • Division of Structural Biology

Hidekazu Hiroaki [Professor]

http://presat-vector.org/hiroaki-lab/

Outline of Seeds

(Objective)
Tight Junction (TJ) is an adhesion machinery at the apical membrane of epithelial and endothelial cells. We focused scaffold proteins interacting with C-terminus of claudins, which are the adhesive molecules in TJ. Because their scaffold proteins involve in the formation and disappearance of TJ, we consider that small compounds which inhibit the interaction between scaffold proteins and claudins could controll TJ.
(Overview)
Among scaffold proteins, we targeted LNX1 that induces the endocytosis of claudins in TJ. Then, small molecules that could bind LNX1 and inhibit the interaction between LNX1 and claudin were searched by in silico screening. The binding of the candidate compound with LNX1 was confirmed by using NMR method. Moreover, when the cultured epithelial cells were exposed to these compounds, the amount of claudin localized to TJ significantly increased. Hence, these results demonstrate that these compounds are able to control (enhance) the TJ.

Novelty and originality of this research

Application and research area for Industry collaboration

(Commercialization)
- Skin moisturizer
- Symptom relief of inflammatory bowel disease
- Acceleration of the production of epithelial cells for pharmaceuticals assay model
(Ripple effect on the local economy)
A mission of Graduate school of Pharmaceutical Sciences in Nagoya University will be the core of pharmaceutical and biotechnological industries and promote them in Tokai region. We want to contribute to the region by establishing new technology of "Intestinal permeability test of pharmaceutics", which is a basic technology in the process of drug discovery, and organizing a center of drug development.
(Prospects for practical use)
Currently, a compound is provided to company A (major pharmaceutical company) and requested for the evaluation as a reagent.

Key Takeaway

A drug that acts via an innovating mechanism

Keywords

tight junction, cell biology, cell adhesion molecules, pharmaceutical permeability, barrier functions

Technologies

  • in silico screening, NMR-based protein analysis technology, cell-based assay technology

Equipment

  • LINUX workstation, NMR spectrometer, fluorescence microscopy

Monographs, Papers and Articles

  • Fujiwara Y, Goda N, Tamashiro T, Narita H, Satomura K, Tenno T, Nakagawa A, Oda M, Suzuki M, Sakisaka T, Takai Y, Hiroaki H.*, 2015, Crystal structure of afadin PDZ domain–nectin-3 complex shows the structural plasticity of the extended ligand-binding site. Protein Sci., 2015, 24(3):376-385 DOI: 10.1002/pro.2628
  • Tenno, T., Goda, N., Umetsu, Y., Furuse, M., Ota, M., Kinoshita, K., and Hiroaki, H*. 2013. Accidental interaction between PDZ domains and diclofenac revealed by NMR-guided virtual screening. Molecules, 18:9567-9581. doi:10.3390/molecules18089567
  • Umetsu, Y., Taniguchi, R., Satomura, R., Goda, N., Ikegami, T., Furuse, M., and Hiroaki, H*. 2011. 1H, 13C, and 15N resonance assignment of the first PDZ domain of mouse ZO-1. Biomol. NMR Assign 5 (2): 207-210.