Peptide Macrocycles as PPI Inhibitors

sulfoxide pi designs

Inhibiting transcription factor-PPIs via sulfur-mediated non-covalent interactions using macrocyclic peptides

To develop cell-permeable peptide inhibitors against PPIs, my lab is exploiting thioether bridged  macrocyclization strategies on synthetic peptides.  An advantage of including sulfur in the macrocyclic bridge is the ability to modulate the sulfur oxidation state from thioethers to sulfoxides, sulfones, and sulfonium ions. We are designing thioether-containing peptide macrocycles for tuning peptide-protein interactions and enhancing helical and proteolytic stability. In these experiments, projects employ significant unnatural amino acid synthesis, solid phase peptide chemistry, protein biochemistry and applied biophysics for characterizing protein-ligand interactions. We recently demonstrated the approach against the KIX:MLL interaction and seek to design cell permeable chemical probes for studying this PPI’s role in allosteric regulation of blood disorders and memory formation.  

In collaborative work, we have identified a new non-covalent interaction with aromatic amino acids at protein surfaces with our collaborator Prof. Jonathan Sachs, a sulfoxide-pi interaction reported in Nat. Chem. Biol.  This interaction augments the list of known sulfur-aryl noncovalent interactions including thioether and sulfonium-aromatic interactions. We are further testing this interaction in model systems and studying its relevance in PPIs found in neurological disorders. 

For further reading see

2. “Tuning sulfur oxidation states on thioether-bridged peptide macrocycles for modulation of protein interactions.” G. T. Perell, R. Staebell, A. Cembran, W. C. K. Pomerantz*, ChemBioChem 2017, 18, 1836-44

 1. “Oxidation increases the strength of the methionine-aromatic interaction.”, A. K. Lewis, A. Cembran, T. L. Senkow, R. Mahling, G. T. Perell, M. R. McCarthy, C. Her, B. T. Horn, C. C. Valley, C. B. Karim, J. Gao, W. C. K. Pomerantz, D. D. Thomas, A. Hinderliter, J. N. Sachs*, Nature Chem. Biol. 2016, 12, 860-6