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Grafted Coiled-Coil Peptides as Multivalent Scaffolds for Protein Recognition.

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Self-assembled peptides offer a novel approach to inhibiting protein-protein interactions (PPIs). Dimeric coiled-coil scaffolds show promise for developing targeted cancer therapies by inhibiting MCL-1.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Self-assembled peptides are valuable for designing protein-protein interaction (PPI) inhibitors.
  • MCL-1, an antiapoptotic protein, is a key target in oncology.
  • Coiled-coil scaffolds offer tunable properties for inhibitor design.

Purpose of the Study:

  • To design and evaluate tunable coiled-coil scaffolds as inhibitors of MCL-1.
  • To investigate the impact of oligomerization, multivalency, and cooperativity on PPI inhibition.
  • To explore the potential of these scaffolds in targeting alpha-helix-mediated PPIs.

Main Methods:

  • Grafting hot-spot residues from NOXA-B onto coiled-coil scaffolds.
  • Creating homo- and heterodimeric coiled-coil peptides.
  • Assessing inhibitor potency and selectivity using biophysical methods.
  • Utilizing AlphaFold2 for structural modeling.

Main Results:

  • Engineered dimeric coiled-coil peptides achieved mid-nanomolar potency and selectivity against MCL-1 over BCL-xL.
  • Positive cooperativity was observed in the binding of homodimeric coiled coils to MCL-1, stabilizing both partners.
  • Higher-order oligomers (trimers, tetramers) showed reduced inhibitory potency.
  • Complex interplay between coiled-coil oligomerization and target binding was identified.

Conclusions:

  • Dimeric coiled-coil scaffolds are the most effective for developing inhibitors of alpha-helix-mediated PPIs.
  • This study provides a foundation for designing novel peptide-based therapeutics targeting MCL-1.
  • Understanding the role of oligomerization is crucial for optimizing PPI inhibitor design.