G quadruplexes are secondary structures formed by guanine-rich DNA and RNA sequence motifs. Growing evidence implicates G quadruplexes in a wide variety of cellular processes, most notably in regulation of gene expression at numerous stages (e.g. transcription, splicing and translation). Given the biological importance of G quadruplexes, considerable effort is currently directed toward development of synthetic molecules that can bind and perturb the function of these structures. In contrast to the more common strategy of developing small molecule ligands that recognize quadruplexes based on shape, we are pursuing a sequence-targeted approach involving peptide nucleic acid oligomers. In one format, the PNA is complementary to the target. Upon invasion of the quadruplex structure, a PNA-DNA or PNA-RNA heteroduplex is formed. In a second format, the PNA is itself G-rich and invades quadruplex DNA or RNA to form heteroquadruplex structures. Biophysical and biochemical experiments will be presented showing low nanomolar K<sub>D</sub> and IC<sub>50</sub> values for quadruplex-targeted PNAs. The benefits of using a second-generation PNA analogue, gammaPNA, will also be presented.

Sequence-targeted invasion of DNA and RNA G quadruplexes by peptide nucleic acid

255th National Meeting (2018)

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