title: Design of a selenylsulfide-bridged EGFR dimerization arm mimic.
abstract: 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 β-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 β-loop peptides for disruption of protein-protein interactions.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, 240 W. Green St., Athens, GA 30602, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Hanold
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, 240 W. Green St., Athens, GA 30602, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Watkins
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, 240 W. Green St., Athens, GA 30602, USA.
authors.forename: Norman T
authors.initials: NT
authors.lastname: Ton
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, 240 W. Green St., Athens, GA 30602, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Liaw
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, 240 W. Green St., Athens, GA 30602, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Beedle
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, 240 W. Green St., Athens, GA 30602, USA. Electronic address: ekennedy@uga.edu.
authors.forename: Eileen J
authors.initials: EJ
authors.lastname: Kennedy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D015195:Drug Design; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D060066:Protein Interaction Maps / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects*; D055550:Protein Stability; D012643:Selenium / Q000737:chemistry* / Q000494:pharmacology; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D010455:Peptides; D057786:Peptidomimetics; D013440:Sulfides; D066246:ErbB Receptors; D012643:Selenium
keywords: Cyclization; Dimerization; EGFR; Peptide; Selenylsulfide
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