Eisai R&d Management Co., Ltd.

National Institute of Advanced Industrial Science and Technology

Eisai Company, Limited

Mamiko Tsuchiya

Kappei Tsukahara

Norihiro Ueda

Keigo Tanaka

Itaru Tsukada

Kazutaka Nakamoto

Katsura Hata

Koji Sagane

Naoaki Watanabe

Fuminori Ohba

Junko Kai

Yoshifumi Jigami

Kenichi Nakayama

Mariko Umemura

Michiyo Okamoto

The present invention enables screening for compounds that inhibit the transport of GPI-anchored proteins to fungal cell walls, using a simple assay for transacylation to GlcN-PI using membrane fraction expressing GWT1 protein. New antifungal agents can be created that inhibit the synthesis of fungal cell walls and also inhibit adhesion to host cells by inhibiting the transport of GPI-anchored proteins to fungal cell walls.

Method of screening for compounds that inhibit the enzymatic activity of GWT1 gene product

The present invention provides isolated DNA encoding a GWT1 protein having activity to confer resistance of a fungus against a compound of formula Ia, and wherein a defect of a function of the GWT1 protein leads to a decrease in the amount of a glycosylphosphatidylinositol (GPI)-anchored protein in the cell wall of a fungus.

Fungal cell wall synthesis gene

A reporter system reflecting the transport process that transports GPI-anchored proteins to the cell wall was constructed and compounds inhibiting this process were discovered. Further, fungal genes conferring resistance to the above compounds were identified and methods of screening for compounds that inhibit the activity of the proteins encoded by these genes were developed. These genes encode proteins participating in fungal cell wall synthesis. Therefore, through the novel compounds, the present invention showed that antifungal agents having a novel mechanism, i.e. inhibiting the process that transports GPI-anchored proteins to the cell wall, could be achieved.

A reporter system reflecting the transport process that transports GPI-anchored proteins to the cell wall was constructed and compounds inhibiting this process were discovered. Further, genes conferring resistance to the above compounds were identified and methods of screening for compounds that inhibit the activity of the proteins encoded by these genes were developed. Therefore, through the novel compounds, the present invention showed that antifungal agents having a novel mechanism, i.e. inhibiting the process that transports GPI-anchored proteins to the cell wall, could be achieved.

Growing community of inventors

Ushiku, Japan

Mamiko Tsuchiya