Mini review: protein-protein interactions in transcription: a fertile ground for helix mimetics

Abstract

Designed ligands that inhibit protein-protein interactions involved in gene expression are valuable as reagents for genomics research and as leads for drug discovery efforts. Selective modulation of protein-protein interactions has proven to be a daunting task for synthetic ligands; however, the last decade has seen significant advances in inhibitor design, especially for helical protein interfaces. This review discusses examples of transcriptional complexes targeted by designer helices.

Figure 1

The DNA-protein and protein-protein interactions provide attractive targets for the design of inhibitors and activators of gene expression. (i) Programmable sequence-specific DNA binding ligands, such as pyrrole-imidazole polyamides, represent a successful class of synthetic modulators of transcription. (ii) Emerging strategies for targeting protein-protein interactions are offering new approaches for the design of transcription regulators.

Figure 2

Side chain crosslinks and hydrogen bond surrogates provide two successful methods for stabilizing the helical conformation in peptides. Crosslinking of residues on the same face of the helix enhances helix stability. Hydrogen bond surrogate (HBS) helices feature a covalent bond in place of the intramolecular hydrogen bond to initiate helix formation. Green circles represent amino acid side chain functionality.

Figure 3

Miniature proteins that display stable helical folds and regulate transcription: (a) avian pancreatic protein (PDB code: 1ppt), (b) scorpion toxin miniprotein (PDB code: 1r1g), and (c) apamin (PDB code: 3iux).

Figure 4

α-Helix and β-peptide foldamers array side chain functionality in similar fashion: (a) primary and (b) secondary structures of α- and β-peptide helices (Cambridge Structural Database accession code 633286).

Figure 5

Nonpeptidic helix mimetics such as (b) terphenyls and (c) pyridylpyridone derivatives array protein like functionality to mimic their arrangement on an α-helix.