Possibilities and challenges of small molecule organic compounds for the treatment of repeat diseases
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...
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| Published in | Proceedings of the Japan Academy, Series B Vol. 98; no. 1; pp. 30 - 48 |
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| Main Author | |
| Format | Journal Article |
| Language | English |
| Published |
Japan
The Japan Academy
01.01.2022
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0386-2208 1349-2896 1349-2896 |
| DOI | 10.2183/pjab.98.003 |
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| Abstract | 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. |
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| AbstractList | 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. 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. 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.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. |
| ArticleNumber | PJA9801B-03 |
| Author | NAKATANI, Kazuhiko |
| Author_xml | – sequence: 1 fullname: NAKATANI, Kazuhiko organization: SANKEN, The Institute of Scientific and Industrial Research, Osaka University |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/35013029$$D View this record in MEDLINE/PubMed |
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| Keywords | hairpin neurological diseases small molecule trinucleotide repeat mismatch expansion |
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| Snippet | 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... |
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| SubjectTerms | Ataxia Binding Biocompatibility Brain research Chemists Deoxyribonucleic acid DNA expansion Fibroblasts Gene sequencing Genes Genomes hairpin Humans Huntington's disease Huntingtons disease mismatch Myotonic dystrophy Myotonic Dystrophy - genetics Nervous System Diseases Neurological diseases Nucleotide sequence Organic chemistry Organic compounds Polyglutamine Proteins Review Ribonucleic acid RNA RNA-binding protein small molecule Spinocerebellar Ataxias - genetics trinucleotide repeat Trinucleotide repeat diseases Trinucleotide Repeat Expansion Trinucleotide repeats X chromosomes |
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| Title | Possibilities and challenges of small molecule organic compounds for the treatment of repeat diseases |
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