posted on 2024-03-02, 17:27authored byAndreas Berner, Rabindra Nath Das, Naresh Bhuma, Justyna Golebiewska, Alva Abrahamsson, Måns Andréasson, Namrata Chaudhari, Mara Doimo, Partha Pratim Bose, Karam Chand, Roger Strömberg, Sjoerd Wanrooij, Erik Chorell
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.