Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 23, Issue 12, Pages 2761-2766Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.03.040
Keywords
Selenylsulfide; Peptide; Cyclization; EGFR; Dimerization
Funding
- NIH [1K22CA154600]
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The epidermal growth factor receptor (EGFR) dimerization arm is a key feature that stabilizes dimerization of the extracellular receptor, thereby mediating activation of the tyrosine kinase domain. Peptides mimicking this b-loop feature can disrupt dimer formation and kinase activation, yet these peptides lack structural constraints or contain redox sensitive disulfide bonds which may limit their stability in physiological environments. Selenylsulfide bonds are a promising alternative to disulfide bonds as they maintain much of the same structural and chemical behavior, yet they are inherently less prone to reduction. Herein, we describe the synthesis, stability and activity of selenylsulfide-bridged dimerization arm mimics. The synthesis was accomplished using an Fmoc-based strategy along with C-terminal labeling for improved overall yield. This selenylsulfide-bridged peptide displayed both proteolytic stability and structural stability even under reducing conditions, demonstrating the potential application of the selenylsulfide bond to generate redox stable beta-loop peptides for disruption of protein-protein interactions. (C) 2015 Elsevier Ltd. All rights reserved.
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