Improved performances of catalytic G-quadruplexes (G4-DNAzymes) vi a the chemical modifications of the DNA backbone to provide G-quadruplexes 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 be more 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 AG(4)A and AG(6)A to obtain d((3')AGG(5')-(5')GGA(3')) (or AG(2)-G(2)A) and d((3')AGG(5')-(5')GGA(3')) (or AG(3)-G(3)A) that fold into stable G4 whose tetramolecular nature was confirmed via nuclear magnetic resonance (NMR) and circular dichroism (CD) investigations. Both AG(2)-G(2)A and AG(3)-G(3)A 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 perform hemoprotein-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. (C) 2019 Elsevier B.V. All rights reserved.