Double Stranded DNA Binding Stapled Peptides: An Emerging Tool for Transcriptional Regulation

Stapled peptides have rapidly established themselves as a powerful technique to mimic α‐helical interactions with a short peptide sequence. There are many examples of stapled peptides that successfully disrupt α‐helix‐mediated protein‐protein interactions, with an example currently in clinical trials. DNA‐protein interactions are also often mediated by α‐helices and are involved in all transcriptional regulation processes. Unlike DNA‐binding small molecules, which typically lack DNA sequence selectivity, DNA‐binding proteins bind with high affinity and high selectivity. These are ideal candidates for the design DNA‐binding stapled peptides. Despite the parallel to protein‐protein interaction disrupting stapled peptides and the need for sequence specific DNA binders, there are very few DNA‐binding stapled peptides. In this review we examine all the known DNA‐binding stapled peptides. Their design concepts are compared to stapled peptides that disrupt protein‐protein interactions and based on the few examples in the literature, DNA‐binding stapled peptide trends are discussed. DNA‐binding proteins regulate key cellular processes through sequence selective high affinity interactions of an α‐helix with the major groove of DNA. These α‐helices provide a starting point in designing DNA‐binding stapled peptides. This review examines all known DNA‐binding stapled peptides and analyzes their features and trends.