Protein elongation factor 2 as a target for antifungal and antiparasitic agents
AssigneeMerck & Co., Inc.
InventorsJennifer Nielsen-Kahn, Michael C. Justice, Dennis M. Schmatz, Ming-Jo Hsu, Theresa W. Ku
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Abstract
Inhibition of protein elongation factor 2 provides a target for identifying potential antifungal and antiparasitic compounds. EF2 inhibitors are useful as therapeutic agents against fungal and parasitic infections.
Claims19
A method of identifying compounds which selectively inhibit fungal or parasitic protein synthesis by impairing the function of the fungal or parasitic elongation factor 2 (EF2).
EF2 as a specific target for antifungal and antiparasitic agents.
A method for identifying a compound which inhibits EF2 comprising
- (a) adding a compound to a genetically engineered eukaryotic organism capable of detecting pathogen selective effects on EF2 function, and
- (b) determining whether said compound inhibits protein synthesis by assaying growth inhibition.
A method for identifying a compound which selectively inhibits EF2 which comprises
- (a) constructing fungal or protozoan cells that express a heterologous EF2 from fungal and parasitic pathogens;
- (b) inoculating cells into liquid or onto solid growth medium containing test compounds or fermentation extracts;
- and
- (c) quantitating the minimal inhibitory concentration (MIC) of the test compound to completely inhibit growth in liquid or the measurement of an inhibitory zone on a solid substrate.
A method for identifying a compound which inhibits EF2 comprising
- (a) plating a known dilution of cells on the appropriate medium;
- (b) contacting said cells with a known dilution of a test compound or natural product extract;
- (c) incubating said cells at about 30° C. for about 16 to 24 hours;
- and
- (d) quantitating the percent of growth inhibition specific for loss of EF2 function due to the test compound or natural product extract.
A modified Saccharomyces cerevisiae cell wherein the cell expresses a heterologous EF2.
A method for identifying compounds having antifungal activity comprising:
- (a) contacting EF2 or an extract containing EF2 with a known amount of a labeled compound that interacts with EF2;
- (b) contacting said EF2 or said extract with a known dilution of a test compound or a natural product extract;
- and
- (c) quantitating the percent inhibition of interaction of said labeled compound induced by said test compound.
A method for the treatment or prevention of fungal diseases comprising administering to a host a therapeutically or prophylactically effective amount of a compound which inhibits EF2 function of the fungi.
A method for the treatment or prevention of parasitic diseases comprising administering to a host a therapeutically or prophylactically effective amount of a compound which inhibits EF2 function of the parasite.
A composition useful for the prevention or treatment of fungal diseases which comprises an inert carrier and an effective amount of a compound that selectively impairs fungal or parasitic EF2 function.
Dependencies are inferred from the claim text.