Screening for Rnase L Activators

描述（由申请人提供）：RNase L是一种普遍表达的潜在核糖核酸酶，其被2-5A（2 '，5'连接的寡腺苷酸）天然激活。RNA酶L介导干扰素的抗病毒和促凋亡活性。最近，它也被定位为遗传性前列腺癌（HPC 1）的候选基因。在这项研究中，导致酶活性丧失或降低的RNASEL突变与前列腺癌早发和恶性进展的风险较高相关。总之，这些观察结果表明，RNase L是病毒感染和癌症治疗的重要药物靶标。为了利用RNase L的治疗价值，我们建议通过使用适合于高通量筛选的改进的荧光共振能量转移测定来从小分子化学文库中筛选RNase L激活剂。所得无毒且有活性的RNase L激活剂将是潜在的抗前列腺癌治疗剂和广谱抗病毒剂。前列腺癌是50岁以上男性中最具破坏性的癌症，在美国每年导致约200，000例新发病例和30，000例死亡。病毒感染日益受到关注，这是由于最近在世界范围内爆发了新出现的病毒（如西尼罗河病毒和SARS），对此没有有效的治疗方法，也是由于生物恐怖主义的风险日益增加。该项目的成功完成将为目前难治性癌症和病毒感染开辟一个全新的治疗类别，利用人体天然免疫的重要途径。

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.