SK 872. Tools for the Discovery of New Antifungal Drugs by Targeting Essential mRNA Cap Formation

Summary of Invention

This invention provides methods and reagents for the discovery of molecules that target an essential aspect of eukaryotic gene expression -- the formation of the mRNA 5' cap. This target is relevant since cap synthesis is essential for the growth of pathogenic fungal species.

The invention is based on developed isogenic yeast strains that differ solely on the source of their essential cap-forming enzymes, originated either from Saccharomyces, Candida, or mammalian species. These strains form the basis of a differential growth inhibition assay to identify molecules that specifically target the fungal but not the mammal capping apparatus.

Provided also is a method to screen in vitro for molecules that inhibit fungal RNA triphosphatase, an essential enzyme that catalyzes the first of three steps in cap synthesis.

Advantages

Provides a new target to screen and develop new antifungals that can be more potent than current drugs and will allow treatment of increasingly resistant fungal strains.

Stage of Development

Ready for use. The following tools are provided:

• Yeast strains containing Saccharomyces, Candida, or mammalian capping enzymes.
• Yeast expression plasmids bearing the genes encoding the Saccharomyces, Candida, and mammalian capping enzymes.
• Bacterial expression plasmids for each of the components of the Saccharomyces, Candida, and mammalian capping systems (the recombinant proteins are His-tagged to facilitate rapid purification) with validated purification protocols and assay procedures.

Lead Inventor

Dr. Stewart Shuman

Patent Information

• US patents 6,107,040, 6,232,070, and 6,420,163.
• PCT national phase patent application published WO0063433, filed in Australia (Issued No. 762713), Canada, Europe, Japan and Mexico.

References

• Pei Y, et al. BMC Microbiol. 1(1):29 (2001).
• Saha N, et al. J Biol Chem. 274(23):16553-62 (1999).
• Ho CK, et al. J Biol Chem. 273:34151-34156 (1998).

Contact Information

Julia Calonge, PhD
Tel: 212-639-6181; Fax: 212-717-3934
E-mail: calongej@mskcc.org