Dysregulation in the protein-protein interactions, PPIs, of transcriptional components, such as coactivators and activators, profoundly affects gene expression and is prominent in disease. Coactivators act as regulators of gene expression by bridging activators engaged at enhancer regions of genes to the general transcription machinery. Thus, modulation of gene expression through the inhibition of these PPIs is an avenue to define the role that dysregulated networks play in the development of disease. Due to the intricacy in targeting these complexes, peptidomimetic molecules have the potential to be developed into selective and potent inhibitors.

Here, we report the development of a target-adjustable lipopeptide inhibitor of activator-coactivator complexes based on transcriptional activation domain, TAD, sequences of activators. Structure-activity relationship studies demonstrate adjustability in the selectivity of lipopeptide analogs for various coactivators, including Med25 and CBP/p300. We identified specific moieties on the lipopeptide that dictate the selective disruption of coactivator-activator PPIs. Additionally, the binding mode of potent inhibitors to their main target was determined using 2D NMR.

Our results suggest the occurrence of specific interactions between lipopeptide residues and coactivators, which are crucial for the activity and selectivity of these lipopeptides. Our data positions this molecule as a platform with modifiable selectivity, and it proposes lipopeptides as a novel scaffold for the selective inhibition and characterization of coactivator PPI networks.