Office of Technology Development

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

SK 872

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

Area of Application

Research tool for drug discovery

Stage of Development

Ready for use. The following tools also are available for licensing:

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

Stewart Shuman, MD, PhD

Patent Information

U.S. patents issued:

References

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

Contact Information

Jeanne Farrell, PhD
Tel: 212-639-6181; Fax: 212-717-3934
E-mail: farrelj1@mskcc.org

Categories

Research Tools

assay (A-say)

A laboratory test to find and measure the amount of a specific substance.

Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)

drug (drug)

Any substance, other than food, that is used to prevent, diagnose, treat or relieve symptoms of a disease or abnormal condition. Also refers to a substance that alters mood or body function, or that can be habit-forming or addictive, especially a narcotic.

Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)

enzyme (EN-zime)

A protein that speeds up chemical reactions in the body.

Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)

gene (jeen)

The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein.

Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)

mRNA

A type of RNA found in cells. mRNA molecules carry the genetic information needed to make proteins. They carry the information from the DNA in the nucleus of the cell to the cytoplasm where the proteins are made. Also called messenger RNA.

Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)

recombinant (ree-KOM-bih-nunt)

In genetics, describes DNA, proteins, cells, or organisms that are made by combining genetic material from two different sources. Recombinant substances are made in the laboratory and are being studied in the treatment of cancer and for many other uses.

Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)

RNA

One of two types of nucleic acid made by cells. RNA contains information that has been copied from DNA (the other type of nucleic acid). Cells make several different forms of RNA, and each form has a specific job in the cell. Many forms of RNA have functions related to making proteins. RNA is also the genetic material of some viruses instead of DNA. RNA can be made in the laboratory and used in research studies. Also called ribonucleic acid.

Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)

SAHA

A drug that is used to treat cutaneous T-cell lymphoma that does not get better, gets worse, or comes back during or after treatment with other drugs. It is also being studied in the treatment of other types of cancer. SAHA is a type of histone deacetylase inhibitor. Also called suberoylanilide hydroxamic acid, vorinostat, and Zolinza.

Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)

will (wil)

A legal document in which a person states what is to be done with his or her property after death, who is to carry out the terms of the will, and who is to care for any minor children.

Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)