Some of the most significant therapies that treat disease target nucleic acids. Drugs that target nucleic acid include cancer drugs, antibiotics, and antivirals. Combined these classes of drugs have annual sales worldwide of ~$139 billion. Antibiotics that target nucleic acids account for $14.5 billion of the $42 billion of sales annuall for all antibiotics, and account for three of the top five classes of antibiotics. The crisis of antibiotic resistance has resulted in a significant cost, both financially and in human life. Seveny percent of infectious bacteria are resistant to at least one commonly used antibiotic treatment (NIH). In the United States alone, 1.7 million people get an infection while in a hospital environment with just under 100,000 of these cases resulting in death (NIH). This situation demonstrates the increased need for the development of new antibiotic therapies. A rapid assay examining the binding affinity of novel aminoglycosides to the A-site and other nucleic acid sites will facilitate the discovery of effective therapies. In Phase I, we have developed a fluorescence based competition assay using a 27-base RNA model of the ribosomal A-site and a novel fluorescent reporter molecule, F-neo. This assay is readily adaptable to a high throughput format as larger compound libraries are established. In Phase II our specific aims are 1) develop an automated fluorescent based assay for screening broad based RNA targets.
This aim i ncludes expanding the current assay to a high throughput automated screen and adapting the assay to include other nucleic acid drug targets. 2) Expand the library of aminoglycoside conjugated molecules. Phase I resulting in a small in house compound library that was screened using the assay developed in Phase I. In Phase II the library will be greatly expanded by the conjugation of aminoglycosides with different classes of compounds using a variety of linker lengths and types. 3) Screening of NUBAD compounds to determine and characterize the activity. This in vivo assay will help establish a correlation between hits from the assay and activity in the cell. At the conclusion of this work, we will have established a commercially available assay for the high throughput screening of compounds that target nucleic acids. This technology will fill a niche in the high throughput screening industry, and result in more efficien development of compounds that treat disease related to nucleic acid therapies.
Some of the most significant therapies that treat disease target nucleic acids. A rapid assay examining the binding affinity of nucleic acid will facilitate he discovery of effective therapies. At the conclusion of this work, we will have established a commercially available assay for the high throughput screening of compounds that target nucleic acids. This technology will fill a niche in the high throughput screening industry, and result in more efficient development of compounds that treat disease related to nucleic acid therapies.
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