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Targeting the ALS/FTD-associated A-DNA kink with anthracene-based metal complex causes DNA backbone straightening and groove contraction.
- Source :
-
Nucleic acids research [Nucleic Acids Res] 2021 Sep 20; Vol. 49 (16), pp. 9526-9538. - Publication Year :
- 2021
-
Abstract
- The use of a small molecule compound to reduce toxic repeat RNA transcripts or their translated aberrant proteins to target repeat-expanded RNA/DNA with a G4C2 motif is a promising strategy to treat C9orf72-linked disorders. In this study, the crystal structures of DNA and RNA-DNA hybrid duplexes with the -GGGCCG- region as a G4C2 repeat motif were solved. Unusual groove widening and sharper bending of the G4C2 DNA duplex A-DNA conformation with B-form characteristics inside was observed. The G4C2 RNA-DNA hybrid duplex adopts a more typical rigid A form structure. Detailed structural analysis revealed that the G4C2 repeat motif of the DNA duplex exhibits a hydration shell and greater flexibility and serves as a 'hot-spot' for binding of the anthracene-based nickel complex, NiII(Chro)2 (Chro = Chromomycin A3). In addition to the original GGCC recognition site, NiII(Chro)2 has extended specificity and binds the flanked G:C base pairs of the GGCC core, resulting in minor groove contraction and straightening of the DNA backbone. We have also shown that Chro-metal complexes inhibit neuronal toxicity and suppresses locomotor deficits in a Drosophila model of C9orf72-associated ALS. The approach represents a new direction for drug discovery against ALS and FTD diseases by targeting G4C2 repeat motif DNA.<br /> (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Subjects :
- Amyotrophic Lateral Sclerosis genetics
Amyotrophic Lateral Sclerosis pathology
Anthracenes chemistry
Anthracenes pharmacology
Coordination Complexes chemistry
Coordination Complexes pharmacology
DNA drug effects
DNA ultrastructure
DNA, A-Form drug effects
Frontotemporal Dementia genetics
Frontotemporal Dementia pathology
Humans
Nucleic Acid Conformation drug effects
Small Molecule Libraries pharmacology
Amyotrophic Lateral Sclerosis drug therapy
C9orf72 Protein genetics
DNA, A-Form ultrastructure
Frontotemporal Dementia drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1362-4962
- Volume :
- 49
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Nucleic acids research
- Publication Type :
- Academic Journal
- Accession number :
- 33836081
- Full Text :
- https://doi.org/10.1093/nar/gkab227