Improved performances of catalytic G-quadruplexes (G4-DNAzymes) via the chemical modifications of the DNA backbone to provide Gquadruplexes with double 3′-external G-quartets

Here we report on the design of a new catalytic G-quadruplex-DNA system (G4-DNAzyme) based on the modification of the DNA scaffold to provide the DNA pre-catalyst with two identical 3′-ends, known to bemore catalytically proficient than the 5′-ends. To this end, we introduced a 5′-5′ inversion of polarity site in the middle of the G4-forming sequences AG4A andAG6A to obtain d(3′AGG5′-5′GGA3′) (orAG2-G2A) and d(3′AGGG5′-5′GGGA3′) (or AG3-G3A) that fold into stable G4 whose tetramolecular nature was confirmed via nuclear magnetic resonance (NMR) and circular dichroism(CD) investigations. Both AG2-G2AandAG3-G3A display two identical external G-quartets (3′-ends) known to interact with the cofactor hemin with a high efficiency, making the resulting complex competent to performhemoprotein-like catalysis (G4-DNAzyme). A systematic comparison of the performances of modified and unmodified G4s lends credence to the relevance of the modification exploited here (5′-5′ inversion of polarity site), which represents a new chemical opportunity to improve the overall activity of catalytic G4s.