Tuning Sulfur Oxidation States on Thioether-Bridged Peptide Macrocycles for Modulation of Protein Interactions

Gabriella T. Perell, Rachel Lynn Staebell, Mehrdad Hairani, Alessandro Cembran, William C.K. Pomerantz

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1836-1844
Number of pages9
JournalChemBioChem
Volume18
Issue number18
DOIs
StatePublished - Sep 19 2017

Fingerprint

Sulfides
Sulfur
Myeloid-Lymphoid Leukemia Protein
Tuning
Modulation
Sulfoxides
Lactams
Oxidation
Peptides
Protein Stability
Hydrocarbons
Solubility
Protein Kinases
Proteins
Ions
Amino Acids

Keywords

  • peptide macrocycles
  • peptidomimetics
  • protein–protein interactions
  • stapled peptides
  • sulfur oxidation

Cite this

Tuning Sulfur Oxidation States on Thioether-Bridged Peptide Macrocycles for Modulation of Protein Interactions. / Perell, Gabriella T.; Staebell, Rachel Lynn; Hairani, Mehrdad; Cembran, Alessandro; Pomerantz, William C.K.

In: ChemBioChem, Vol. 18, No. 18, 19.09.2017, p. 1836-1844.

Research output: Contribution to journalArticle

@article{0977ed134e5a467790f0ea982002c47c,
title = "Tuning Sulfur Oxidation States on Thioether-Bridged Peptide Macrocycles for Modulation of Protein Interactions",
abstract = "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.",
keywords = "peptide macrocycles, peptidomimetics, protein–protein interactions, stapled peptides, sulfur oxidation",
author = "Perell, {Gabriella T.} and Staebell, {Rachel Lynn} and Mehrdad Hairani and Alessandro Cembran and Pomerantz, {William C.K.}",
year = "2017",
month = "9",
day = "19",
doi = "10.1002/cbic.201700222",
language = "English (US)",
volume = "18",
pages = "1836--1844",
journal = "ChemBioChem",
issn = "1439-4227",
publisher = "Wiley-VCH Verlag",
number = "18",

}

TY - JOUR

T1 - Tuning Sulfur Oxidation States on Thioether-Bridged Peptide Macrocycles for Modulation of Protein Interactions

AU - Perell, Gabriella T.

AU - Staebell, Rachel Lynn

AU - Hairani, Mehrdad

AU - Cembran, Alessandro

AU - Pomerantz, William C.K.

PY - 2017/9/19

Y1 - 2017/9/19

N2 - 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.

AB - 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.

KW - peptide macrocycles

KW - peptidomimetics

KW - protein–protein interactions

KW - stapled peptides

KW - sulfur oxidation

UR - http://www.scopus.com/inward/record.url?scp=85028919558&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85028919558&partnerID=8YFLogxK

U2 - 10.1002/cbic.201700222

DO - 10.1002/cbic.201700222

M3 - Article

C2 - 28631349

AN - SCOPUS:85028919558

VL - 18

SP - 1836

EP - 1844

JO - ChemBioChem

JF - ChemBioChem

SN - 1439-4227

IS - 18

ER -