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Context-sensitive cleavage of folded DNAs by loop-targeting bPNAs.

Herein, we demonstrate context-dependent molecular recognition of DNA by synthetic bPNA iron and copper complexes, using oxidative backbone cleavage as a chemical readout for binding. Oligoethyleneimine bPNAs displaying iron-EDTA or copper-phenanthroline sites were found to be efficient chemical nucleases for designed and native structured DNAs with T-rich single-stranded domains. Cleavage reactivity depends strongly on structural context, as strikingly demonstrated with DNA substrates of the form (GGGTTA)n. This repeat sequence from the human telomere is known to switch between parallel and antiparallel G-quadruplex (G4) topologies upon changing from potassium to sodium buffer: notably, bPNA-copper complexes efficiently cleave long repeat sequences into ~22 nt portions in sodium-but not potassium buffer. We hypothesize preferential cleavage of the antiparallel topology (Na+) over the parallel (K+) due to greater accessibility of the TTA loop to bPNA in the antiparallel (Na+) form. Similar ion-sensitive telomere shortening upon treatment with bPNA nucleases can be observed in both isolated and intracellular DNA from PC3 cells by qPCR. Live cell treatment was accompanied by accelerated cellular senescence, as expected for significant telomere shortening. Taken together, the loop-targeting approach of bPNA chemical nucleases complements prior intercalation strategies targeting duplex and quadruplex DNA. Structurally-sensitive loop-targeting enables discrimination between similar target sequences, thus expanding bPNA targeting beyond simple oligo-T sequences. Further, bPNA nucleases are cell membrane permeable, and therefore may be used to target native intracellular substrates. In addition, these data indicate that bPNA scaffolds can be a platform for new synthetic binders to particular nucleic acid structural motifs.