Tools
Tools
D'Anna, Luisa, Wragg, Darren, Mauro, Daniela, Rubino, Simona, Terenzi, Alessio, Barone, Giampaolo, Thomas, Sophie R. 
ORCID: https://orcid.org/0000-0003-1110-430X, Casini, Angela, Bonsignore, Riccardo and Spinello, Angelo
(2025)
Unraveling the Molecular Basis for G-Quadruplex-Binders to ALS/FTD-Associated G4C2 Repeats of the C9orf72 Gene.
ChemBioChem, 26 (8).
ISSN 1439-4227
Preview |
PDF (ChemBioChem - 2024 - D'Anna - Unraveling the Molecular Basis for G‐Quadruplex‐Binders to ALS FTD‐Associated G4C2 Repeats of)
- Published Version
Available under License Creative Commons Attribution. Download (1MB) | Preview |
Abstract
The most recurrent familial cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of an abnormal number of intronic GGGGCC (G4C2) repetitions in the C9orf72 gene, which has been proposed to drive ALS/FTD pathogenesis. Recently, it has been shown that such G4C2 repetitions can fold into G-quadruplex (G4) secondary structures. These G4s have been selectively stabilized by small-molecule binders, furnishing proof-of-principle that targeting these non-canonical nucleic acid sequences represents a novel and effective therapeutic strategy to tackle neurodegenerative disorders. However, precise information on the mechanism of action of these compounds is still lacking. Here, by performing in silico investigations, we unraveled the molecular basis for the selectivity of a series of known structurally related C9orf72 G4-binders. Moreover, we investigated the binding properties of a strong and selective metal-based G4 stabilizer, the AuI bis-N-heterocyclic carbene (NHC) complex – Au(TMX)2 – showing that it moderately stabilizes G4C2 G4 RNA by Förster resonance energy transfer (FRET) DNA melting assays. Using metadynamics (metaD) simulations, the Au(TMX)2 binding mode and the associated free-energy landscape were also evaluated. This information paves the way for developing improved compounds to tackle ALS/FTD neurodegenerative disorders.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | c9orf72,g-quadruplex,docking,molecular dynamics,neurodegenerative disorders,biochemistry,molecular medicine,molecular biology,organic chemistry ,/dk/atira/pure/subjectarea/asjc/1300/1303 |
| Faculty \ School: | Faculty of Science > School of Chemistry, Pharmacy and Pharmacology |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 16 Sep 2026 15:28 |
| Last Modified: | 21 Sep 2026 23:03 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/104569 |
| DOI: | 10.1002/cbic.202400974 |
Downloads
Downloads per month over past year
Actions (login required)
 |
View Item |