title: A perfluoroaryl-cysteine S(N)Ar chemistry approach to unprotected peptide stapling.
abstract: We report the discovery of a facile transformation between perfluoroaromatic molecules and a cysteine thiolate, which is arylated at room temperature. This new approach enabled us to selectively modify cysteine residues in unprotected peptides, providing access to variants containing rigid perfluoroaromatic staples. This stapling modification performed on a peptide sequence designed to bind the C-terminal domain of an HIV-1 capsid assembly polyprotein (C-CA) showed enhancement in binding, cell permeability, and proteolytic stability properties, as compared to the unstapled analog. Importantly, chemical stability of the formed staples allowed us to use this motif in the native chemical ligation-mediated synthesis of a small protein affibody that is capable of binding the human epidermal growth factor 2 receptor.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Spokoyny
authors.forename: Yekui
authors.initials: Y
authors.lastname: Zou
authors.forename: Jingjing J
authors.initials: JJ
authors.lastname: Ling
authors.forename: Hongtao
authors.initials: H
authors.lastname: Yu
authors.forename: Yu-Shan
authors.initials: YS
authors.lastname: Lin
authors.forename: Bradley L
authors.initials: BL
authors.lastname: Pentelute
mesh_terms: D036022:Capsid Proteins / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D003432:Cross-Linking Reagents; D003545:Cysteine / Q000031:analogs & derivatives / Q000737:chemistry*; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D005466:Fluorocarbons / Q000737:chemistry; D015497:HIV-1 / Q000737:chemistry; D006801:Humans; D007202:Indicators and Reagents; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D010539:Permeability; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014325:Tromethamine
chemical_list: D036022:Capsid Proteins; D003432:Cross-Linking Reagents; D003545:Cysteine; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D005466:Fluorocarbons; D007202:Indicators and Reagents; D008024:Ligands; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D013438:Sulfhydryl Compounds; D014325:Tromethamine; C545158:cysteine thiolate; C508053:ERBB2 protein, human
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