De Novo Modular Development of a Foldameric Protein-Protein Interaction Inhibitor for Separate Hot Spots

A Dynamic Covalent Assembly Approach

Éva Bartus, Zsófia Hegedüs, Edit Wéber, Brigitta Csipak, G. Szakonyi, T. Martinek

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Protein-protein interactions stabilized by multiple separate hot spots are highly challenging targets for synthetic scaffolds. Surface-mimetic foldamers bearing multiple recognition segments are promising candidate inhibitors. In this work, a modular bottom-up approach is implemented by identifying short foldameric recognition segments that interact with the independent hot spots, and connecting them through dynamic covalent library (DCL) optimization. The independent hot spots of a model target (calmodulin) are mapped with hexameric β-peptide helices using a pull-down assay. Recognition segment hits are subjected to a target-templated DCL ligation through thiol-disulfide exchange. The most potent derivative displays low nanomolar affinity towards calmodulin and effectively inhibits the calmodulin-TRPV1 interaction. The DCL assembly of the folded segments offers an efficient approach towards the denovo development of a high-affinity inhibitor of protein-protein interactions.

Original languageEnglish
JournalChemistryOpen
DOIs
Publication statusAccepted/In press - 2017

Fingerprint

Calmodulin
Proteins
Bearings (structural)
Sulfhydryl Compounds
Scaffolds
Disulfides
Assays
Derivatives
Peptides

Keywords

  • Dynamic covalent chemistry
  • Foldamers
  • Molecular recognition
  • Peptidomimetics
  • Protein-protein interactions

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

De Novo Modular Development of a Foldameric Protein-Protein Interaction Inhibitor for Separate Hot Spots : A Dynamic Covalent Assembly Approach. / Bartus, Éva; Hegedüs, Zsófia; Wéber, Edit; Csipak, Brigitta; Szakonyi, G.; Martinek, T.

In: ChemistryOpen, 2017.

Research output: Contribution to journalArticle

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