Optimization of the Linker Domain in a Dimeric Compound that Degrades an r(CUG) Repeat Expansion in Cells

RNA repeat expansions
are responsible for more than 30 incurable
diseases. Among them is myotonic dystrophy type 1 (DM1), the most
common form of adult on-set muscular dystrophy. DM1 is caused by an
r­(CUG) repeat expansion [r­(CUG)exp] located in the 3′
untranslated region (UTR) of the dystrophia myotonica protein kinase
gene. This repeat expansion is highly structured, forming a periodic
array of 5′CUG/3′GUC internal loop motifs. We therefore designed dimeric
compounds that simultaneously bind two of these motifs by connecting
two RNA-binding modules with peptoid linkers of different geometries
and lengths. The optimal linker contains two proline residues and
enhances compound affinity. Equipping this molecule with a bleomycin
A5 cleaving module converts the simple binding compound into a potent
allele-selective cleaver of r­(CUG)exp. This study shows
that the linker in modularly assembled ligands targeting RNA can be
optimized to afford potent biological activity.