From transcription factors to designed sequence-specific DNA-binding peptides

Transcription factors are DNA-binding proteins responsible for initiating the transcription of particular genes upon interacting with specific DNA sequences located at their promoter or enhancer regions. The DNA recognition process. which is extremely selective. is mediated by noncovalent interactions between appropriately arranged structural motifs of the protein and exposed surfaces of the DNA bases and backbone. The great variability in DNA recognition by transcription factors has hampered the characterization of an amino acid-base step recognition code, making it very difficult to design non-natural peptides that can mimic the DNA-binding properties of these naturally occurring counterparts. However, in recent years, several transcription factor-based miniature proteins capable of tight interaction with specific DNA sites have been successfully constructed, most of them using bottom-up synthetic approaches.