Why the study?
RNA repeat expansions cause more than 30 neurological and neuromuscular diseases with no known cures, warranting therapeutic strategies using bifunctional small molecules to selectively cleave aberrant RNA.
Replacing bleomycin A5 with deglycobleomycin in Cugamycin enhances selectivity and reduces DNA damage while maintaining efficacy in cleaving disease-causing RNA repeats in DM1 models.
RNA repeat expansions cause more than 30 neurological and neuromuscular diseases with no known cures. Since repeat expansions operate via diverse pathomechanisms, one potential therapeutic strategy is to rid them from disease-affected cells, using bifunctional small molecules that cleave the aberrant RNA. Such an approach has been previously implemented for the RNA repeat that causes myotonic dystrophy type 1 [DM1, r(CUG) exp ] with Cugamycin, which is a small molecule that selectively binds r(CUG) exp conjugated to a bleomycin A5 cleaving module. Herein, we demonstrate that, by replacing bleomycin A5 with deglycobleomycin, an analogue in which the carbohydrate domain of bleomycin A5 is removed, the selectivity of the resulting small-molecule conjugate (DeglycoCugamycin) was enhanced, while maintaining potent and allele-selective cleavage of r(CUG) exp and rescue of DM1-associated defects. In particular, DeglycoCugamycin did not induce the DNA damage that is observed with high concentrations (25 μM) of Cugamycin, while selectively cleaving the disease-causing allele and improving DM1 defects at 1 μM.
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Angelbello et al. (2020) studied Myotonic dystrophy type 1 (DM1). DeglycoCugamycin vs. Cugamycin was evaluated on Cleavage of r(CUG)exp and rescue of DM1-associated defects.
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