Structural insights into synthetic ligands targeting A-A pairs in disease-related CAG RNA repeats.

Sanjukta Mukherjee,Asako Murata,Leszek Błaszczyk,Wojciech Rypniewski,Christoph Falschlunger,Agnieszka Kiliszek,Kazuhiko Nakatani,Ronald Micura,Chikara Dohno

doi:10.1093/nar/gkz832

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.

Highlights

Microsatellites or short tandem repeats (STR) are highly abundant sequences scattered throughout the human genome [1]
We have developed cyclic mismatch-binding ligands (CMBLs) composed of two naphthyridine rings connected by two linkers, which were found to interact with CAG repeats [32,33] (Figure 1A)
The models show details of the ligand binding, local and nonlocal effects on the RNA structure and interactions with the solvent, which should be useful for developing therapeutics against trinucleotide repeat expansion disorders (TREDs)

Summary

Introduction

Microsatellites or short tandem repeats (STR) are highly abundant sequences scattered throughout the human genome [1]. The main type of repeats found within genes is the trinucleotide CNG repeats (N stands for one of the four nucleotides). They are characterized by an instability, which can lead to their expansion [2]. If the number of CNG repeats exceeds a certain threshold, they become pathogenic [3,4,5]. More than 40 hereditary neurodegenerative human disorders, classified collectively as TREDs (tri-nucleotide repeat expansion disorders), are associated with the expansion of the trinucleotide repeats [3,5]. A quarter of them result from the expansion of CAG repeats

Methods

Results

Conclusion