Peptide nucleic acid (PNA) and its applications in chemical biology, diagnostics, and therapeutics

Peptide nucleic acid (PNA) stands as one of the most successful artificial oligonucleotide mimetics. Salient features include the stability of hybridization complexes (either as duplexes or triplexes), metabolic stability, and ease of chemical modifications. These features have enabled important applications such as antisense agents, gene editing, nucleic acid sensing and as a platform to program the assembly of PNA-tagged molecules. Here, we review recent advances in these areas

Biosupramolecular Systems: Integrating Cues into Responses

Life is orchestrated by biomolecules interacting in complex networks of biological circuitry with emerging function. Progress in different areas of chemistry has made the design of systems that can recapitulate elements of such circuitry possible. Herein we review prominent examples of networks, the methodologies available to translate an input into various outputs, and speculate on potential applications and directions for the field. The programmability of nucleic acid hybridization has inspired applications beyond its function in heredity. At the circuitry level, DNA provides a powerful platform to design dynamic systems that respond to nucleic acid input sequences with output sequences through diverse logic gates, enabling the design of ever more complex circuitry. In order to interface with more diverse biomolecular inputs and yield outputs other than oligonucleotide sequences, an array of nucleic acid conjugates have been reported that can engage proteins as their input and yield a turn-on of enzymatic activity, a bioactive small molecule, or morphological changes in nanoobjects. While the programmability of DNA makes it an obvious starting point to design circuits, other biosupramolecular interactions have also been demonstrated, and harnessing progress in protein design is bound to deliver further integration of macromolecules in artificial circuits

Suprastapled Peptides: Hybridization-Enhanced Peptide Ligation and Enforced α-Helical Conformation for Affinity Selection of Combinatorial Libraries

Stapled peptides with an enforced α-helical conformation have been shown to overcome major limitations in the development of short peptides targeting protein–protein interactions (PPIs). While the growing arsenal of methodologies to staple peptides facilitates their preparation, stapling methodologies are not broadly embraced in synthetic library screening. Herein, we report a strategy leveraged on hybridization of short PNA–peptide conjugates wherein nucleobase driven assembly facilitates ligation of peptide fragments and constrains the peptide's conformation into an α-helix. Using native chemical ligation, we show that a mixture of peptide fragments can be combinatorially ligated and used directly in affinity selection against a target of interest. This approach was exemplified with a focused library targeting the p-53/MDM2 interaction. One hundred peptides were obtained in a one-pot ligation reaction, selected by affinity against MDM2 immobilized on beads, and the best binders were identified by mass spectrometry