Optimization of the Linker Domain in a Dimeric Compound that Degrades an r(CUG) Repeat Expansion in Cells.
Raphael I BenhamouMasahito AbeShruti ChoudharySamantha M MeyerAlicia J AngelbelloMatthew D DisneyPublished in: Journal of medicinal chemistry (2020)
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.
Keyphrases
- muscular dystrophy
- protein kinase
- induced apoptosis
- high resolution
- nucleic acid
- anti inflammatory
- cell cycle arrest
- dna binding
- type diabetes
- healthcare
- genome wide
- high throughput
- cancer therapy
- transcription factor
- binding protein
- duchenne muscular dystrophy
- young adults
- adipose tissue
- copy number
- glycemic control
- signaling pathway
- metabolic syndrome
- skeletal muscle
- cell death
- dna methylation
- single cell