Eisai R&d Management Co., Ltd.

Eisai Company, Limited

Koji Sagane

Keigo Tanaka

Itaru Tsukada

Kazutaka Nakamoto

Kappei Tsukahara

Katsura Hata

Norihiro Ueda

Naoaki Watanabe

Mamiko Tsuchiya

Fuminori Ohba

Junko Kai

Kaoru Ogawa

Toshihiro Horii

Kazuto Yamazaki

Eiki Takahashi

Turo Oki

It is an object of the present invention to provide a non-human gene-disrupted animal with a disrupted ADAM11 gene. According to the present invention, a non-human gene-disrupted animal, wherein either one of or both alleles of an ADAM11 gene are disrupted, is provided.

Non-human gene-disrupted animal with disrupted ADAM11 gene

The present inventors succeeded in isolating GWT1 (PfGWT1), which is one of the enzymes involved in GPI biosynthesis in the malaria parasite. In addition, the inventors revealed that degenerate mutant DNAs, with a lower AT content than the DNA encoding the PfGWT1 protein, can complement the phenotype of GWT1-deficient yeast. Based on the findings, the present invention provides the GWT1 protein of malaria parasites and the use of the protein in methods of screening for antimalarial drugs. The present invention also provides degenerate mutant DNAs encoding proteins involved in GPI biosynthesis, and which have a lower AT content than the original DNAs. The present invention also provides methods of screening for antimalarial drugs which use the degenerate mutant DNAs.

Methods of screening for compounds that inhibit the biosynthesis of GPI in malaria parasites

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

Tsukuba, Japan

Koji Sagane