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Hydrophobic cross-linking of peptides to create inhibitors of protein-protein interactions

Hydrophobic cross-linking of peptides at critical binding residues could help generate stable, peptide-based inhibitors of protein-protein interactions involving irregular, non-alpha helical interfaces. X-ray crystallography of the interaction between Pseudomonas aeruginosa exoenzyme S (exoS) and human 14-3-3 protein identified critical binding residues in an 11-amino-acid peptide sequence of exoS. Replacement of two exoS residues with non-natural amino acids followed by cross-linking via a hydrophobic bridge increased the peptide's binding affinity for 14-3-3 compared with the natural peptide sequence. In vitro, the best-modified cross-linked peptide decreased the binding interaction between exoS and 14-3-3 more than the natural peptide. Next steps include optimizing the peptides for cell membrane permeability and cellular activity.

SciBX 7(12); doi:10.1038/scibx.2014.355
Published online March 27, 2014

Patent filed by the Max Planck Society; available for licensing

Glas, A. et al. Angew. Chem. Int. Ed.; published online Feb. 6, 2014;
Contact: Tom N. Grossmann, Chemical Genomics Centre of the Max Planck Society, Dortmund, Germany
Contact: Christian Ottmann, Eindhoven University of Technology, Eindhoven, the Netherlands