Screening for Rnase L Activators

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DESCRIPTION (provided by applicant): RNase L is a ubiquitous expressed latent ribonuclease, which is naturally activated by 2-5A (2',5' linked oligoadenylate). RNase L mediates antiviral and proapoptotic activities of interferon. Recently, it has also been mapped to a candidate gene for hereditary prostate cancer (HPC1). In this study, RNASEL mutations that result in the loss or reduction in enzymatic activity were associated with a higher risk for early onset and malignant progress of prostate cancer. Taken together, these observations suggest that RNase L is an important drug target for viral infections and cancer therapy. To harness the therapeutic value of RNase L, we propose to screen for RNase L activators from a small molecule chemical library by using an improved fluorescence resonance energy transfer assay adapted for high-throughput screening. The resulting nontoxic and active RNase L activator(s) will be a potential anti-prostate cancer therapeutic and a broad-spectrum anti-viral agent. Prostate cancer is the most devastating cancer in men over the age of 50, resulting in about 200,000 new cases and 30,000 deaths per year in the U.S. There is currently no highly effective therapy for late-stage metastatic, hormone-refractory prostate cancer. Viral infections are of increasing concern due to recent outbreaks worldwide (such as West Nile Virus and SARS) of emerging viruses for which there are no effective therapies and due to the perceived increasing risks of bioterrorism. The successful completion of this proposed project will open a whole new class of therapy for currently intractable cancer and viral infections leveraging an important pathway of the body's natural immunity.