Open AccessOptimization of the Linker Domain in a Dimeric Compound that Degrades an r(CUG) Repeat Expansion in Cells
Author(s) -
Raphael I. Benhamou,
Masahito Abe,
Sonal Choudhary,
Samantha M. Meyer,
Alicia J. Angelbello,
Matthew D. Disney
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c00558
Subject(s) - linker , myotonic dystrophy , trinucleotide repeat expansion , chemistry , rna , untranslated region , peptoid , binding site , gene , genetics , microbiology and biotechnology , biochemistry , biophysics , stereochemistry , biology , allele , peptide , computer science , operating system
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'C U G/3'G U C 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.