A Minimal Synthetic Cleavage Module Enables Selective Degradation of Pathogenic r(CUG) Repeats in Cells

Although direct RNA degradation offers an alternative to occupancy-driven activity, it has relied on complex natural product-derived cleavage modules such as bleomycin. Here, we show that a compact synthetic Fe(II)-coordinating warhead can be programmed for selective RNA degradation in cells. Coupling this cleavage module to a small molecule that recognizes expanded r(CUG) repeats that cause myotonic dystrophy type 1 (DM1) afforded selective degradation of the pathogenic RNA while sparing wild type and transcripts harboring short r(CUG) repeats. In DM1 patient-derived myoblasts, degradation of mutant repeat RNA reduced DM1-associated pathology including formation of nuclear foci, sequestration of MBNL1, and alternative pre-mRNA splicing defects, without inducing DNA damage. These studies establish that minimal synthetic cleavage modules can replace complex natural product warheads to enable selective degradation of disease-causing RNAs in cells.