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Structural insights into synthetic ligands targeting A-A pairs in disease-related CAG RNA repeats
Sanjukta Mukherjee1, Leszek Błaszczyk2, Wojciech Rypniewski2
1Department of Regulatory Bioorganic Chemistry, The Institute of Scientific and Industrial Research, Osaka University 8-1 Mihogaoka, Ibaraki 567-0047, Japan.
Abstract:
The trinucleotide repeat expansion disorders (TREDs) constitute of a group of >40 hereditary neurodegenerative human diseases associated with abnormal expansion of repeated sequences, such as CAG repeats. The pathogenic factor is a transcribed RNA or protein whose function in the cell is compromised. The disorders are progressive and incurable. Consequently, many ongoing studies are oriented at developing therapies. We have analyzed crystal structures of RNA containing CAG repeats in complex with synthetic cyclic mismatch-binding ligands (CMBLs). The models show well-defined interactions between the molecules in which the CMBLs mimic nucleobases as they form pseudo-canonical base pairs with adenosine residues and engage in extensive stacking interactions with neighboring nucleotides. The binding of ligands is associated with major structural changes of the CAG repeats, which is consistent with results of biochemical studies. The results constitute an early characterization of the first lead compounds in the search for therapy against TREDs. The crystallographic data indicate how the compounds could be further refined in future biomedical studies.
Insights
Researchers explored cyclic mismatch-binding ligands (CMBLs) for trinucleotide repeat expansion disorders (TREDs). These ligands bind to CAG repeat RNA, showing potential as early therapeutic leads for these neurodegenerative diseases.
Area of Science:
- Biochemistry
- Structural Biology
- Neurogenetics
Background:
- Trinucleotide repeat expansion disorders (TREDs) are a class of over 40 hereditary neurodegenerative diseases.
- These progressive and incurable conditions result from abnormal expansions of DNA repeats, like CAG, leading to cellular dysfunction.
- Current research focuses on developing effective therapies for TREDs.
Purpose of the Study:
- To analyze the structural interactions of synthetic cyclic mismatch-binding ligands (CMBLs) with CAG repeat RNA.
- To characterize the initial lead compounds for potential TRED therapies.
Main Methods:
- X-ray crystallography was used to determine the structures of CAG repeat RNA in complex with CMBLs.
- Biochemical studies were conducted to validate the observed binding interactions and structural changes.
Main Results:
- Crystal structures revealed well-defined interactions where CMBLs mimic nucleobases, forming pseudo-canonical base pairs with adenosine.
- CMBLs engage in extensive stacking interactions with adjacent nucleotides within the RNA structure.
- Ligand binding induced significant structural alterations in the CAG repeat RNA, correlating with biochemical findings.
Conclusions:
- The study presents the first characterization of CMBLs as potential therapeutic lead compounds for TREDs.
- Crystallographic data provide insights for refining these compounds in future biomedical research.
- These findings represent a promising step towards developing treatments for neurodegenerative diseases caused by repeat expansions.
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