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Tuning Sulfur Oxidation States on Thioether‐Bridged Peptide Macrocycles for Modulation of Protein Interactions
Author(s) -
Perell Gabriella T.,
Staebell Rachel Lynn,
Hairani Mehrdad,
Cembran Alessandro,
Pomerantz William C. K.
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700222
Subject(s) - thioether , peptide , sulfur , chemistry , combinatorial chemistry , modulation (music) , stereochemistry , biochemistry , organic chemistry , physics , acoustics
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.