Combining G‐Quadruplex Targeting Motifs on a Single Peptide Nucleic Acid Scaffold: A Hybrid (3+1) PNA–DNA Bimolecular Quadruplex

Abstract

Abstract:We describe the first Gquadruplex targeting approach that combines an intercalation and a hybridization strategy by investigating the interaction of a G-rich PNA acridone conjugate 1 with a three repeat fragment of the human telomere G3 to form a hybrid PNA-DNA quadruplex mimicking the biologically relevant (3+1) pure DNA dimeric telomeric quadruplex. Using a combination of UV, CD and fluorescence spectroscopy as well as mass spectrometry, we show that PNA 1 can induce the formation of a bimolecular hybrid quadruplex even at low salt concentration upon interaction with a single-stranded three repeat fragment of telomeric DNA. However PNA 1 cannot invade a short fragment of B-DNA even if the latter contains a CCC motif complementary to the PNA sequence. These studies could open up new possibilities for the design of a novel generation of quadruplex ligands that target not only the external features of the quadruplex but also its central core constituted by the tetrads themselves.

Noncovalent binding and fluorogenic response of cyanine dyes to DNA homoquadruplex and PNA-DNA heteroquadruplex structures

“…An alternative strategy relies on sequence-based recognition, where complementary C-rich oligonucleotides bind via Watson-Crick base pairing to form heteroduplexes [7][8][9][10] or homologous G-rich oligonucleotides bind via Hoogsteen-based G-tetrad formation to yield heteroquadruplexes. [11][12][13][14][15] Peptide nucleic acid (PNA) probes can bind to G-quadruplexes by either of these mechanisms, leading to stable hybrid structures.…”

“…In our prior work, we used a covalently conjugated fluorogenic cyanine dye to provide a fluorescence response to PNA binding, as in the "light-up" probes originally reported by Ishiguro and coworkers for DNA 17 and subsequently by Svanvik and coworkers for PNA. 18,19 Recently, Ladame and coworkers 15 combined a PNA G 3 tract that could form one edge of a heteroquadruplex with an acridone stacking ligand previously shown to end-stack on G-tetrads. 20 Although the examples cited above clearly illustrate that a covalently conjugated dye can interact with a PNA-DNA heteroquadruplex, it was unclear to what extent the dye would interact with the heteroquadruplex if not for the covalent linkage to the PNA terminus.…”

Structural and Energetic Impact of Non-Natural 7-Deaza-8-Azaadenine and Its 7-Substituted Derivatives on H-Bonding Potential with Uracil in RNA Molecules

“…[1][2][3][4][5][6] This large functional repertoire is also due to the fact that, in addition to the four canonical nucleotides, adenine (A), uracil (U), guanine (G) and cytosine (C), naturally occurring RNAs may feature a variety of over 100 post-transcriptional modificatons, 7 greatly enhancing their chemical information and functional capability. Modification of the nucleobases [8][9][10][11] and of the ribose-phosphate [12][13][14][15] backbone can have an impact on the stability, kinetics, and resistance to enzymatic degradation of nucleic acid molecules. 16,17 Recently, non natural (synthetic) modifications have been introduced to complement the natural ones.…”

Hybridization of short complementary PNAs to G‐quadruplex forming oligonucleotides: An electrospray mass spectrometry study

“…[26][27][28][29][30] In this context, we have investigated the interaction between several QFOs, each containing one or more TGGGGT motif, and the short complementary [ac 4 a]-PNA. QFOs can adopt a variety of folds differing mainly by the number of the DNA strands involved and the relative orientation of the strands into the resulting G-quadruplexes (parallel or antiparallel orientation).…”