G4-ligand-conjugated oligonucleotides mediate selective binding and stabilization of individual G4 DNA structures

Umeå universitet, Institutionen för medicinsk kemi och biofysik Umeå universitet, Kemiska institutionen Department of Biosciences and Nutrition, Karolinska Institutet, Neo, Huddinge, Sweden Department of Biosciences and Nutrition, Karolinska Institutet, Neo, Huddinge, Sweden 2024

G-quadruplex (G4) DNA structures are prevalent secondary DNA structures implicated in fundamental cellular functions, such as replication and transcription. Furthermore, G4 structures are directly correlated to human diseases such as cancer and have been highlighted as promising therapeutic targets for their ability to regulate disease-causing genes, e.g., oncogenes. Small molecules that bind and stabilize these structures are thus valuable from a therapeutic perspective and helpful in studying the biological functions of the G4 structures. However, there are hundreds of thousands of G4 DNA motifs in the human genome, and a long-standing problem in the field is how to achieve specificity among these different G4 structures. Here, we developed a strategy to selectively target an individual G4 DNA structure. The strategy is based on a ligand that binds and stabilizes G4s without selectivity, conjugated to a guide oligonucleotide, that specifically directs the G4-Ligand-conjugated oligo (GL-O) to the single target G4 structure. By employing various biophysical and biochemical techniques, we show that the developed method enables the targeting of a unique, specific G4 structure without impacting other off-target G4 formations. Considering the vast amount of G4s in the human genome, this represents a promising strategy to study the presence and functions of individual G4s but may also hold potential as a future therapeutic modality.

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy); Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci); Article in journal; info:eu-repo/semantics/article; text

10.1021.jacs.3c14408

Open access content. Open access content
info:eu-repo/semantics/openAccess

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UPE oai:DiVA.org:umu-222294
0000-0001-6347-2169
0009-0004-3292-1637
0000-0001-8089-2333
0000-0001-7691-4392
0000-0001-6126-4382
0000-0003-2523-1940
doi:10.1021/jacs.3c14408
PMID 38430200
ISI:001179314400001
Scopus 2-s2.0-85186374110
1428119410

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