Targeting nucleic acids with a G-triplex-to-G-quadruplex transformation and stabilization using a peptide–PNA G-tract conjugate

Abstract

A dual-functional peptide–PNA (peptide nucleic acid) conjugate consisting of a PNA G3-tract and an RHAU23 peptide is devised to target nucleic acids bearing three tandem guanine tracts (G-tracts). The PNA G3-tract joins the three G-tracts to form a stable bimolecular G-quadruplex (G4) and the resulting G4 is then bound by the RHAU23 moiety to form an extra stable G4–peptide complex. Owing to this synergistic dual structural enforcement, the conjugate accomplished extremely high selectivity and nM to sub-nM affinities towards its targets that are up to 1000 times greater than the small molecule G4 ligands. As a result, the conjugate impacts the tracking activity of motor proteins on DNA with superior selectivity and potency that are rarely seen in other G4-targeting approaches.