title: A One-Pot Chemically Cleavable Bis-Linker Tether Strategy for the Synthesis of Heterodimeric Peptides.
abstract: Heterodimeric peptides linked by disulfide bonds are attractive drug targets. However, their chemical assembly can be tedious, time-consuming, and low yielding. Inspired by the cellular synthesis of pro-insulin in which the two constituent peptide chains are expressed as a single-chain precursor separated by a connecting C-peptide, we have developed a novel chemically cleavable bis-linker tether which allows the convenient assembly of two peptide chains as a single "pro"-peptide on the same solid support. Following the peptide cleavage and post-synthetic modifications, this bis-linker tether can be removed in one-step by chemical means. This method was used to synthesize a drug delivery-cargo conjugate, TAT-PKCi peptide, and a two-disulfide bridged heterodimeric peptide, thionin (7-19)-(24-32R), a thionin analogue. To our knowledge, this is the first report of a one-pot chemically cleavable bis-linker strategy for the facile synthesis of cross-bridged two-chain peptides.
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.|School of Chemistry, University of Melbourne, Melbourne, VIC, 3010, Australia.|Bio21 Institute, University of Melbourne, Australia.
authors.forename: Nitin A
authors.identifier: 0000-0003-0422-9411
authors.initials: NA
authors.lastname: Patil
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
authors.forename: Julien
authors.initials: J
authors.lastname: Tailhades
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.|School of Chemistry, University of Melbourne, Melbourne, VIC, 3010, Australia.|Bio21 Institute, University of Melbourne, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Karas
authors.affiliation: School of Chemistry, University of Melbourne, Melbourne, VIC, 3010, Australia.|Bio21 Institute, University of Melbourne, Australia.
authors.forename: Frances
authors.identifier: 0000-0002-6484-2763
authors.initials: F
authors.lastname: Separovic
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.|School of Chemistry, University of Melbourne, Melbourne, VIC, 3010, Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Wade
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.|School of Chemistry, University of Melbourne, Melbourne, VIC, 3010, Australia.
authors.forename: Mohammed Akhter
authors.identifier: 0000-0002-9961-0006
authors.initials: MA
authors.lastname: Hossain
mesh_terms: D004220:Disulfides / Q000737:chemistry; D016503:Drug Delivery Systems; D015394:Molecular Structure; D054809:Thionins / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D004220:Disulfides; D054809:Thionins
keywords: N-terminal linkers; conjugation; heterodimeric peptides; peptides; solid-phase synthesis