The Dimeric Form of 1,3‐Diaminoisoquinoline Derivative Rescued the Mis‐splicing of <i>Atp2a1</i> and <i>Clcn1</i> Genes in Myotonic Dystrophy Type 1 Mouse Model

Matsumoto, Jun; Nakamori, Mikihito; Okamoto, T.; Murata, Akira; Dohno, Chikara; Nakatani, Kazuhiko

doi:10.1002/chem.202001572

Cited by 10 publications

(9 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, they reported a new molecule JM642 consisting of two 1,3-diaminoisoquinoline chromophores with an auxiliary aromatic unit at the C5 position. [60] Through in vitro binding analysis by surface plasmon resonance assay with JM642, the selective and efficient binding to the r(CUG) repeat was observed. The binding to CUG repeats with JM642 inhibited RNA aggregation, releasing trapped splicing factors.…”

Section: Binding Molecules To Tà T/uà U Mismatch Sitesmentioning

confidence: 99%

Selective Chemical Modification to the Higher‐Order Structures of Nucleic Acids

Nagatsugi

Onizuka

2022

The Chemical Record

View full text Add to dashboard Cite

DNA and RNA can adopt a variety of stable higher‐order structural motifs, including G‐quadruplex (G4 s), mismatches, and bulges. Many of these secondary structures are closely related to the regulation of gene expression. Therefore, the higher‐order structure of nucleic acids is one of the candidate therapeutic targets, and the development of binding molecules targeting the higher‐order structure of nucleic acids has been pursued vigorously. Furthermore, as one of the methodologies for detecting the higher‐order structures of these nucleic acids, developing techniques for the selective chemical modification of the higher‐order structures of nucleic acids is also underway. In this personal account, we focus on the following higher‐order structures of nucleic acids, double‐stranded DNA containing the abasic site, T−T/U−U mismatch structure, and G‐quadruplex structure, and describe the development of molecules that bind to and chemically modify these structures.

show abstract

Section: Binding Molecules To Tà T/uà U Mismatch Sitesmentioning

confidence: 99%

Selective Chemical Modification to the Higher‐Order Structures of Nucleic Acids

Nagatsugi

Onizuka

2022

The Chemical Record

View full text Add to dashboard Cite

show abstract

“…NA shortened CAG repeats in the striatum of the brain in an HD mouse model, 45) NCD alleviated the degeneration of compound eyes in a SCA31 Drosophila model, 59) and JM642 alleviated splicing defects in a DM1 mouse model. 64) Although more research is needed, all these compounds are expected to be important leads in the development of effective drugs for alleviating symptoms and even inhibiting the onset of neurodegenerative diseases. Each of these compounds has been shown to bind to a target repeat sequence.…”

Section: Myotonic Dystrophy Typementioning

confidence: 99%

“…76),77),82) On the other hand, the development of heterocycles that bind to thymine (uracil) has not yet been successful in our group. Although JM642 is a characteristic molecule that binds to CUG repeats, 64) its binding mode has not been clarified. In thymine, the sequence of hydrogen bonding groups is Acceptor (A), Donor (D), and Acceptor (A).…”

Section: Design Of Mismatch Binding Moleculesmentioning

confidence: 99%

Possibilities and challenges of small molecule organic compounds for the treatment of repeat diseases

Nakatani

2022

Proceedings of the Japan Academy. Ser. B: Physical and Biologic

Self Cite

View full text Add to dashboard Cite

The instability of repeat sequences in the human genome results in the onset of many neurological diseases if the repeats expand above a certain threshold. The transcripts containing long repeats sequester RNA binding proteins. The mechanism of repeat instability involves metastable slip-out hairpin DNA structures. Synthetic organic chemists have focused on the development of small organic molecules targeting repeat DNA and RNA sequences to treat neurological diseases with repeat-binding molecules. Our laboratory has studied a series of small molecules binding to mismatched base pairs and found molecules capable of binding CAG repeat DNA, which causes Huntington's disease upon expansion, CUG repeat RNA, a typical toxic RNA causing myotonic dystrophy type 1, and UGGAA repeat RNA causing spinocerebellar ataxia type 31. These molecules exhibited significant beneficial effects on disease models in vivo, suggesting the possibilities for small molecules as drugs for treating these neurological diseases.

show abstract

“…This strategy provides a new avenue for DM1 research and suggests an alternative method of repeat-selective screening. A new molecule, JM642, was reported to have the capacity to bind to the expanded r(CUG) repeat and disrupt ribonuclear foci in the C2C12 DM1 cells and HSA LR mice, finally rescuing mis-splicing ( Nakatani et al, 2020 ). Moreover, several potential therapeutic molecules focus on cleaving the aberrant CUG repeats from disease-affected cells.…”

Section: Therapeutic Strategies Of Dm1mentioning

confidence: 99%

Brain Pathogenesis and Potential Therapeutic Strategies in Myotonic Dystrophy Type 1

Liu

Guo

Yan

et al. 2021

Front. Aging Neurosci.

View full text Add to dashboard Cite

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy that affects multiple systems including the muscle and heart. The mutant CTG expansion at the 3′-UTR of the DMPK gene causes the expression of toxic RNA that aggregate as nuclear foci. The foci then interfere with RNA-binding proteins, affecting hundreds of mis-spliced effector genes, leading to aberrant alternative splicing and loss of effector gene product functions, ultimately resulting in systemic disorders. In recent years, increasing clinical, imaging, and pathological evidence have indicated that DM1, though to a lesser extent, could also be recognized as true brain diseases, with more and more researchers dedicating to develop novel therapeutic tools dealing with it. In this review, we summarize the current advances in the pathogenesis and pathology of central nervous system (CNS) deficits in DM1, intervention measures currently being investigated are also highlighted, aiming to promote novel and cutting-edge therapeutic investigations.

show abstract

The Dimeric Form of 1,3‐Diaminoisoquinoline Derivative Rescued the Mis‐splicing of Atp2a1 and Clcn1 Genes in Myotonic Dystrophy Type 1 Mouse Model

Abstract: Figure 1. Chemical structureso fJM608 and the dimeric form JM642.

Cited by 10 publications

References 39 publications

Selective Chemical Modification to the Higher‐Order Structures of Nucleic Acids

Selective Chemical Modification to the Higher‐Order Structures of Nucleic Acids

Possibilities and challenges of small molecule organic compounds for the treatment of repeat diseases

Brain Pathogenesis and Potential Therapeutic Strategies in Myotonic Dystrophy Type 1

Contact Info

Product

Resources

About