Small Molecules that Target the Toxic RNA in Myotonic Dystrophy Type 2

Myotonic dystrophy is the most common form of the adult-onset muscular dystrophy, originating in a CTG repeat expansion in the DMPK gene. The expanded CUG transcript sequesters MBNL1 a key regulator of alternative splicing, leading to the misregulation of numerous pre-mRNAs. We report an RNA-targeted agent as a possible lead compound for the treatment of DM1 that reveals both the promise and challenges for this type of small molecule approach. The agent is a potent inhibitor of the MBNL1-rCUG complex with an inhibition constant, KI of 25 ± 8 nM, and is also relatively non-toxic to HeLa cells, able to dissolve nuclear foci, and correct the IR splicing defect in DM1 model cells. Moreover, treatment with this compound improves two separate disease phenotypes in a DM1 Drosophila model, the adult external eye degeneration and larval crawling defect. However, the compound has a relatively low maximum tolerated dose in mice and its cell uptake may be limited, providing insights into directions for future development.

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“…See the Supporting Information for more details. The cytotoxicity of 2 a was accessed using a published protocol …”

Section: Methodsmentioning

confidence: 99%

A Potent Inhibitor of Protein Sequestration by Expanded Triplet (CUG) Repeats that Shows Phenotypic Improvements in a Drosophila Model of Myotonic Dystrophy

et al. 2016

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“…1A). This molecule contains one aromatic ring and two pyrimidine moieties and was originally designed for inhibiting the formation of the MBNL1-(CCUG) exp protein-RNA complex in myotonic dystrophy type 2 (19). We termed this compound as Anti-polyQ Aggregation for Machado-Joseph-Associated Neurodegeneration (AQAMAN).…”

Section: Aqaman Suppresses Polyq Protein-induced Cell Deathmentioning

confidence: 99%

AQAMAN, a bisamidine-based inhibitor of toxic protein inclusions in neurons, ameliorates cytotoxicity in polyglutamine disease models

Hong

Koon

Chen

et al. 2019

Journal of Biological Chemistry

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Edited by Joseph M. Jez Polyglutamine (polyQ) diseases are a group of dominantly inherited neurodegenerative disorders caused by the expansion of an unstable CAG repeat in the coding region of the affected genes. Hallmarks of polyQ diseases include the accumulation of misfolded protein aggregates, leading to neuronal degeneration and cell death. PolyQ diseases are currently incurable, highlighting the urgent need for approaches that inhibit the formation of disaggregate cytotoxic polyQ protein inclusions. Here, we screened for bisamidine-based inhibitors that can inhibit neuronal polyQ protein inclusions. We demonstrated that one inhibitor, AQAMAN, prevents polyQ protein aggregation and promotes de-aggregation of self-assembled polyQ proteins in several models of polyQ diseases. Using immunocytochemistry, we found that AQAMAN significantly reduces polyQ protein aggregation and specifically suppresses polyQ protein-induced cell death. Using a recombinant and purified polyQ protein (thioredoxin-Huntingtin-Q46), we further demonstrated that AQAMAN interferes with polyQ self-assembly, preventing polyQ aggregation, and dissociates preformed polyQ aggregates in a cell-free system. Remarkably, AQAMAN feeding of Drosophila expressing expanded polyQ disease protein suppresses polyQ-induced neurodegeneration in vivo. In addition, using inhibitors and activators of the autophagy pathway, we demonstrated that AQAMAN's cytoprotective effect against polyQ toxicity is autophagy-dependent. In summary, we have identified AQAMAN as a potential therapeutic for combating polyQ protein toxicity in polyQ diseases. Our findings further highlight the importance of the autophagy pathway in clearing harmful polyQ proteins.

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“…Several examples of small molecules that target r(CCUG) exp and improve DM2-associated defects have been reported (Childs-Disney et al, 2014; Lee et al, 2009b; Nguyen et al, 2014; Rzuczek et al, 2014). Our group reported that the aminoglycoside kanamycin A selectively binds 2×2 5′CU3′/3′UC5′ internal loops.…”

Section: Leveraging Rna Structure To Design Chemical Probes Of Functionmentioning

confidence: 99%

RNA Structures as Mediators of Neurological Diseases and as Drug Targets

Bernat

Disney

2015

Neuron

117

112

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RNAs adopt diverse folded structures that are essential for function and thus play critical roles in cellular biology. A striking example of this is the ribosome, a complex, three-dimensionally folded macromolecular machine that orchestrates protein synthesis. Advances in RNA biochemistry, structural and molecular biology, and bioinformatics have revealed other non-coding RNAs whose functions are dictated by their structure. It is not surprising that aberrantly folded RNA structures contribute to disease. In this review, we provide a brief introduction into RNA structural biology and then describe how RNA structures function in cells and cause or contribute to neurological disease. Finally, we highlight successful applications of rational design principles to provide chemical probes and lead compounds targeting structured RNAs. Based on several examples of well-characterized RNA-driven neurological disorders, we demonstrate how designed small molecules can facilitate study of RNA dysfunction, elucidating previously unknown roles for RNA in disease, and provide lead therapeutics.

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Small Molecules that Target the Toxic RNA in Myotonic Dystrophy Type 2

Cited by 23 publications

References 33 publications

A Potent Inhibitor of Protein Sequestration by Expanded Triplet (CUG) Repeats that Shows Phenotypic Improvements in a Drosophila Model of Myotonic Dystrophy

A Potent Inhibitor of Protein Sequestration by Expanded Triplet (CUG) Repeats that Shows Phenotypic Improvements in a Drosophila Model of Myotonic Dystrophy

AQAMAN, a bisamidine-based inhibitor of toxic protein inclusions in neurons, ameliorates cytotoxicity in polyglutamine disease models

RNA Structures as Mediators of Neurological Diseases and as Drug Targets

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