Recognition of expanded GGGGCC hexanucleotide repeat by synthetic ligand through interhelical binding.

An expanded GGGGCC hexanucleotide (G ₄ C ₂ ) repeat within the non-coding region of C9ORF72 gene has been identified as the most common genetic cause of FTD/ALS kindred, and synthetic ligand targeting this pathological expansion sequence holds a promising approach for the disease interference. We here describe the naphthyridine carbamate tetramer, p-NCTB, as a binding ligand to hairpin G ₄ C ₂ repeat. p-NCTB simultaneously recognizes two distal CGGG/CGGG sites in G ₄ C ₂ repeat DNA and RNA leading to the formation of the interhelical (inter- and intrastrand) binding complexes. The intrastrand binding was predominant when p-NCTB bound to long repeat sequence that accommodates multiple binding sites by folding into hairpins, while the interstrand binding was exclusive for short repeat sequence. The binding of p-NCTB showed repeat-length selectivity: the longer repeat sequence is a better target for p-NCTB. p-NCTB demonstrated inhibition of transcription against G ₄ C ₂ repeat template in vitro in a repeat length-dependent manner.
Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest.
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