Constrained Peptides with Fine‐Tuned Flexibility Inhibit NF‐Y Transcription Factor Assembly.

Jeganathan, Sadasivam; Wendt, Mathias; Kiehstaller, Sebastian; Brancaccio, Diego; Kuepper, Arne; Pospiech, Nicole; Carotenuto, Alfonso; Novellino, Ettore; Hennig, Sven; Grossmann, Tom N.

Protein complex formation depends on the interplay between preorganization and flexibility of the binding epitopes involved. The design of epitope mimetics typically focuses on stabilizing a particular bioactive conformation, often without considering conformational dynamics, which limits the potential of peptidomimetics against challenging targets such as transcription factors. We developed a peptide‐derived inhibitor of the NF‐Y transcription factor by first constraining the conformation of an epitope through hydrocarbon stapling and then fine‐tuning its flexibility. In the initial set of constrained peptides, a single non‐interacting α‐methyl group was observed to have a detrimental effect on complex stability. Biophysical characterization revealed how this methyl group affects the conformation of the peptide in its bound state. Adaption of the methylation pattern resulted in a peptide that inhibits transcription factor assembly and subsequent recruitment to the target DNA.

TRANSCRIPTION factors; PEPTIDES; BOUND states; METHYL groups; NEUROPEPTIDE Y; EPITOPES

Angewandte Chemie, 2019, Vol 131, Issue 48, p17512

0044-8249

Academic Journal

10.1002/ange.201907901