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

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

*Corresponding author for this work

Research output: Contribution to JournalReview articleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)17351-17358
Number of pages8
JournalAngewandte Chemie. International Edition
Issue number48
Early online date20 Sept 2019
Publication statusPublished - 25 Nov 2019

Bibliographical note

© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.


  • constrained peptides
  • peptide inhibitors
  • protein structure
  • protein–DNA interactions
  • protein–protein interactions


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