A simple ligand that selectively targets CUG trinucleotide repeats and inhibits MBNL protein binding

Arambula, Jonathan F.; Ramisetty, Sreenivasa Rao; Baranger, Anne M.; Zimmerman, Steven C.

doi:10.1073/pnas.0901824106

Cited by 207 publications

(251 citation statements)

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“…This demonstrates that the suppression of CUG-dependent phenotypes and recovery of Mbnl1 activity can be achieved without directly competing with Muscleblind binding to CUG repeats but by reducing the fraction of double-stranded CUG RNA from the cellular pool of toxic RNA, hence preventing sequestration of the protein, which requires CUG RNA hairpins. This is a unique mechanism that contrasts with that of other recently characterized molecules that target the binding of MBNL1 to toxic RNAs (17)(18)(19)(20)(21)(22)33). Disrupting Muscleblind binding to RNA could affect its function as a splicing factor in non-CUG-expressing cells.…”

Section: Abp1 Reversed Missplicing and Muscle Histopathology In A Dm1mentioning

confidence: 95%

“…They demonstrated that expanded CTG-induced effects could be reverted if CTG-repeat transgene expression was interrupted in a DM1 mouse model. Several other groups developed synthetic molecules and (CAG)n oligonucleotides that disrupted MBNL1 interaction with expanded CUG repeats (17)(18)(19)(20)(21)(22). However, those approaches may not address all the pathological consequences of expanded CUG RNAs.…”

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confidence: 99%

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In vivo discovery of a peptide that prevents CUG–RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models

Garcia-Lopez

Llamusí

Orzáez

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Myotonic dystrophy type 1 (DM1) is caused by the expansion of noncoding CTG repeats in the dystrophia myotonica-protein kinase gene. Mutant transcripts form CUG hairpins that sequester RNAbinding factors into nuclear foci, including Muscleblind-like-1 protein (MBNL1), which regulate alternative splicing and gene expression. To identify molecules that target toxic CUG transcripts in vivo, we performed a positional scanning combinatorial peptide library screen using a Drosophila model of DM1. The screen identified a D-amino acid hexapeptide (ABP1) that reduced CUG foci formation and suppressed CUG-induced lethality and muscle degeneration when administered orally. Transgenic expression of natural, L-amino acid ABP1 analogues reduced CUG-induced toxicity in fly eyes and muscles. Furthermore, ABP1 reversed muscle histopathology and splicing misregulation of MBNL1 targets in DM1 model mice. In vitro, ABP1 bound to CUG hairpins and induced a switch to a single-stranded conformation. Our findings demonstrate that ABP1 shows antimyotonic dystrophy activity by targeting the core of CUG toxicity.disease model | drug discovery | non-coding RNA disease | medicinal chemistry | RNA secondary structure M yotonic dystrophy type 1 (DM1, OMIM #160900) is an autosomal dominant disease caused by the expansion of a CTG trinucleotide repeat in the 3′ untranslated region (UTR) of the dystrophia myotonica-protein kinase (DMPK) gene. Characteristic symptoms include myotonia, progressive muscle wasting, and cardiac conduction defects, among other systemic manifestations. The molecular mechanisms underlying DM1 pathogenesis are complex and affect a large number of cellular processes (1). However, most data suggest that the main triggering event is a toxic gain-of-function of the expanded CUG RNA. CUG-repeat expansions form double-stranded hairpins that are retained as inclusions within the nucleus. These hairpins recruit a number of transcription and splicing factors, including Muscleblind-like 1 (MBNL1) (2-6). Sequestration of MBNL1 originates a loss of function, which plays a key role in the development of DM1 symptoms. Mbnl1 knockout mice reproduced typical features of DM1, and overexpression of Mbnl1 in a mouse model that expressed CTG repeats reversed these phenotypes (7,8). CTGrepeat expression in mice caused misregulation of at least 156 alternative splicing events. Of these, 128 also occurred in Mbnl1 knockout animals (9-12). The splicing factor CUG-binding protein 1 (CUGBP1) is another key component in the development of DM1 phenotypes. CUGBP1 antagonizes MBNL1 activity in the regulated use of alternative exons in a number of transcripts and is abnormally upregulated in patients with DM1, further contributing to splicing misregulation (13-15).Mahadevan et al. provided the first in vivo proof-of-principle for a therapeutic strategy based on ablating toxic RNA molecules in DM1 (16). They demonstrated that expanded CTG-induced effects could be reverted if CTG-repeat transgene expression was interrupted in a DM1 mouse model. Several ...

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Section: Abp1 Reversed Missplicing and Muscle Histopathology In A Dm1mentioning

confidence: 95%

mentioning

confidence: 99%

In vivo discovery of a peptide that prevents CUG–RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models

Garcia-Lopez

Llamusí

Orzáez

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…These ligands were shown to inhibit the formation of MBNL1 and expanded CUG RNA complexes with high affinity (Pushechnikov et al, 2009). Another group synthesized a ligand with high affinity for CUG RNA repeats, which prevented the aggregation with MBNL1 (Arambula et al, 2009). Perhaps the most comprehensive of these small-molecule approaches involved pentamidine.…”

Section: Destroying or Blocking The Function Of Mutant Dmpk Transcriptsmentioning

confidence: 99%

Tackling the pathogenesis of RNA nuclear retention in myotonic dystrophy

Mastroyiannopoulos

Shammas

Phylactou

2010

Biology of the Cell

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Cyprus DM1 (myotonic dystrophy type I) is a common form of muscular dystrophy that affects mainly adults. It is a disease that belongs to the group of defective RNA export diseases, since a major part of the pathogenic mechanism of the disease is the retention of the mutant transcripts in the cell nucleus. The presence of an expanded CUG trinucleotide repeat in the 3 -UTR (3 -untranslated region) of the DMPK (myotonic dystrophy protein kinase) gene causes the attraction of RNA-binding proteins by the nuclear-located mutant transcripts. As a result of the occupation of the RNA-binding proteins, there is defective mis-splicing of several cellular transcripts. This is believed to be a major pathogenic mechanism of the disease and any attempt to repair the activities of the RNA-binding proteins or target the mutant transcripts should be beneficial for the patients. Certain approaches have been described in the literature and they demonstrate progress in various directions. The purpose of the present review is to summarize the successful attempts to tackle the pathogenesis caused by nuclear retention of mutant transcripts in myotonic dystrophy and to discuss the possible gains from such approaches.

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“…This ligand is a triaminotriazine-acridine conjugate designed to hydrogen bond to both U's or T's in the U-U or T-T mismatch, interactions observed between binding of multi CUG and CTG repeats. This ligand was found to destabilize the interactions of MBNL1 with multi CUG repeats (Arambula et al, 2009). …”

Section: Targeting the Mutant Dmpk Transcriptsmentioning

confidence: 99%