title: A perfluoroaromatic abiotic analog of H2 relaxin enabled by rapid flow-based peptide synthesis.
abstract: H2 relaxin is a pleiotropic peptide hormone with clinical potential. Here we report on the reaction and use of hexafluorobenzene as an intramolecular disulfide replacement between Cys10 and Cys15 in the A-chain of H2 relaxin. Using flow-based Fmoc solid-phase peptide synthesis methodology we were able to obtain high-quality H2 relaxin fragments that were previously reported as challenging to synthesize. Subsequent native chemical ligation and oxidative folding enabled total synthesis of both wild type H2 relaxin and a C6F4 linked analog. Cell-based activity assays revealed modest activity for the C6F4 linked H2 relaxin analog, albeit 100-fold reduced relative to wild type. This work demonstrates how perfluoroarylation-cysteine SNAr chemistry may be a useful tool for the selective replacement of native disulfide bonds in proteins.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. blp@mit.edu.
authors.forename: Tessa
authors.initials: T
authors.lastname: Lühmann
authors.forename: Surin K
authors.initials: SK
authors.lastname: Mong
authors.forename: Mark D
authors.initials: MD
authors.lastname: Simon
authors.forename: Lorenz
authors.initials: L
authors.lastname: Meinel
authors.forename: Bradley L
authors.initials: BL
authors.lastname: Pentelute
mesh_terms: D005466:Fluorocarbons / Q000737:chemistry*; D006859:Hydrogen / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D012065:Relaxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D005466:Fluorocarbons; D006859:Hydrogen; D012065:Relaxin; C003005:hexafluorobenzene