Alterations of protein-protein interaction (PPI) networks involved in the regulation of gene expression can contribute to a myriad of human diseases. The coactivator Med25 of the Mediator Complex , for example, uses PPI networks with transcriptional activators to regulate transcription of stress-response genes and dysregulation of those PPIs is linked to oncogenesis in breast cancer and metastatic phenotypes. There is thus great interest in developing molecular probes to study dysregulated Med25 interactions. One class of natural products, lipopeptides, has demonstrated potent inhibition against Med25 AcID and its cognate binding partners. However, the influence of the lipid tail on potency and selectivity remains unclear. Here we investigate the relationship between the lipid tail structure and the selectivity and potency of the resulting lipopeptide. This is carried out by screening of a collection of derivatives against a panel of transcription coactivators (including Med25) to assess selectivity and potency.

Investigating the role of fatty acid tails in lipopeptide inhibitors of transcriptional coactivators

ACS Spring 2022

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