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

Raphael I. Benhamou, Masahito Abe, Shruti Choudhary, Samantha M. Meyer, Alicia J. Angelbello, Matthew D. Disney*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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.

Original languageAmerican English
Pages (from-to)7827-7839
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number14
StatePublished - 23 Jul 2020
Externally publishedYes

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Publisher Copyright:
© 2020 American Chemical Society.


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