Thioethers, sulfoxides, and sulfonium ions, despite diverse physicochemical properties, all engage in noncovalent interactions with proteins. Thioether-containing macrocycles are also attracting attention as protein–protein interaction (PPI) inhibitors. Here, we used a model PPI between α-helical mixed lineage leukemia (MLL) protein and kinase-inducible domain interacting (KIX) domain to evaluate oxidation effects on sulfurcontaining macrocycle structure, stability, and protein affinity. Desolvation effects from various polarity states were evaluated computationally and experimentally at the side chain, amino acid, and peptide level. Sulfur-containing side chains spanned polarity ranges between all-hydrocarbon and lactam bridges for modulating solubility, cellular uptake, and affinity. Helical propensity studies showed that, although oxidized sulfur-containing side chains could be tolerated, conformational effects were sequence-dependent. In some cases, proteolytic stability, binding capacity with KIX, and increased helicity were obtained as first steps toward developing PPI inhibitors.
Bibliographical noteFunding Information:
The authors acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results reported within this paper. This project was in part funded by an NSF CAREER Award (CHE-1352091) and an American Cancer Society Internal Research Grant (IRG-58-001-55). We thank Anand Divakaran Makenna Ha-begger and Anthony T. Meger for their supporting contributions to peptide synthesis and molecular dynamics simulations and Prof. Alan Kennan for helpful discussion on this study.
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
- peptide macrocycles
- protein–protein interactions
- stapled peptides
- sulfur oxidation