cb0c00036_si_001.pdf (1.72 MB)
Precise Targeted Cleavage of a r(CUG) Repeat Expansion in Cells by Using a Small-Molecule–Deglycobleomycin Conjugate
journal contribution
posted on 2020-03-18, 13:49 authored by Alicia
J. Angelbello, Mary E. DeFeo, Christopher M. Glinkerman, Dale L. Boger, Matthew D. DisneyRNA 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.