Optimization of the Linker Domain in a Dimeric Compound that Degrades an r(CUG) Repeat Expansion in Cells.
| Autor: | Benhamou RI; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States., Abe M; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States., Choudhary S; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States., Meyer SM; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States., Angelbello AJ; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States., Disney MD; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States. |
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| Jazyk: | angličtina |
| Zdroj: | Journal of medicinal chemistry [J Med Chem] 2020 Jul 23; Vol. 63 (14), pp. 7827-7839. Date of Electronic Publication: 2020 Jul 13. |
| DOI: | 10.1021/acs.jmedchem.0c00558 |
| Abstrakt: | 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. |
| Databáze: | MEDLINE |
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