| MECHANISM OF ACTION |
Another group interested in the mechanism of action of RNA-targeted drugs is that of chemistry professor Sidney M. Hecht at the University of Virginia. Hecht and coworkers currently are studying the mechanism by which bleomycin interacts with RNA. Bleomycin, a natural product first isolated in the mid-1960s by Japanese researchers, is used clinically to treat squamous cell carcinoma and malignant lymphoma. The compound has traditionally been thought of as a drug that targets DNA. However, "there's lots of motivation to think that RNA might also be an important therapeutic target for bleomycin," Hecht said at the symposium. After all, it is known to cleave RNA as well as DNA. And it does so with high selectivity--typically cutting just a small number of sites within an RNA molecule. To gain insights into the mechanism of action of bleomycin, Hecht and coworkers are seeking bleomycin analogs that cleave DNA but not RNA--or conversely RNA but not DNA. "To do this, it will be necessary to make large libraries of bleomycin analogs and screen them for bleomycins that are highly selective for RNA or DNA," Hecht said. Hecht and his coworkers have made only small libraries of bleomycin analogs so far. But they intend to synthesize libraries of some 100,000 bleomycins, using split synthesis to create one-compound-per-bead collections. They then plan to screen these libraries for bleomycins that cleave RNA and that don't cleave DNA. "Those that pass both screens represent the type of molecule we think we're going to be interested in" for studies on the mechanism of bleomycin, Hecht said. |
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