A newer approach to studying RNA-mediated diseases, such as myotonic dystrophy type 1 (DM1), involves using small molecules designed to cleave the disease-causing RNA. DM1 is caused by the expanded CUG repeat (r(CUG)exp) in the 3’ untranslated region of the <i>DMPK</i> gene and causes disease by binding and sequestering important regulatory proteins such as MBNL1. A compound that is attached to bleomycin a5, a natural product know to cleave nucleic acids, was found to selectively cleave r(CUG)exp in cells. Bleomycin a5 itself is known to cause DNA cleavage, and the use of bleomycin analogs could potentially reduce off target effects by reducing bleomycin’s affinity for DNA. By using a series of analogs, we investigated the role of the molecule in affecting cleavage and in facilitating uptake. An analog was found that provided a similar level of RNA cleavage but a decrease in DNA cleavage. The new analog also had enhanced cellular permeability. Apparently, modifications can be made to a small molecule that cleaves RNA targets to improve the selectivity of the activity as well as cellular uptake. Further research will focus on studying other bleomycin analogs in order to develop the most efficient and selective small molecule for RNA cleavage.

Investigating the ability of a bleomycin analog to cleave RNA

2019 Spring National Meeting

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