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

Abstract

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.

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BibTeX

@misc{shan2026minimal,
  title = {{A Minimal Synthetic Cleavage Module Enables Selective Degradation of Pathogenic r(CUG) Repeats in Cells}},
  author = {J. Shan and S. Kovachka and K. Sung and M. D. Disney},
  howpublished = {bioRxiv},
  year = {2026},
  month = nov,
  doi = {10.64898/2026.11.04.764312},
  url = {https://www.biorxiv.org/content/10.64898/2026.11.04.764312v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - A Minimal Synthetic Cleavage Module Enables Selective Degradation of Pathogenic r(CUG) Repeats in Cells
AU  - J. Shan
AU  - S. Kovachka
AU  - K. Sung
AU  - M. D. Disney
PY  - 2026
DA  - 2026/11/04
PB  - bioRxiv
DO  - 10.64898/2026.11.04.764312
UR  - https://www.biorxiv.org/content/10.64898/2026.11.04.764312v1
AB  - 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.
ER  -

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