title: High-throughput synthesis of peptide α-thioesters: a safety catch linker approach enabling parallel hydrogen fluoride cleavage.
abstract: Peptide α-thioesters are fundamental building blocks in peptide and protein science, providing powerful tools for peptide medicinal chemistry. The application of peptide α-thioesters in native chemical ligation reactions has enabled synthetic access to cysteine-rich peptides and proteins, cyclic peptides as well as labeled and chemically modified biomolecules. An efficient high-throughput synthesis of peptide α-thioester building blocks would be beneficial for many medicinal chemical applications that require peptides and proteins. Herein we present a novel synthetic route to cysteine-rich peptide α-thioesters using a safety catch linker that enables a parallel synthetic strategy for chemical protein synthesis. ACP(68-75), bradykinin and dynorphin(1-13) were synthesized via Boc chemistry in their thioester form on a safety catch amide linker (SCAL), employing polystyrene- or poly(ethylene glycol)-based resins, compartmentalized in tea bags. This compartmentalized resin/linker strategy facilitated a parallel hydrogen fluoride cleavage in which each peptide thioester was subsequently cyclized by native chemical ligation, demonstrating the utility of this approach. A naturally occurring bioactive cyclic peptide, the sunflower trypsin inhibitor SFTI-1, was synthesized to demonstrate the viability of this method to access important peptide biomolecules.
authors.affiliation: Institute of Molecular Bioscience, The University of Queensland, Brisbane, 4072 (Australia). a.brust@imb.uq.edu.au.
authors.forename: Andreas
authors.initials: A
authors.lastname: Brust
authors.forename: Christina I
authors.initials: CI
authors.lastname: Schroeder
authors.forename: Paul F
authors.initials: PF
authors.lastname: Alewood
mesh_terms: D003500:Cyclization; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry*; D006858:Hydrofluoric Acid / Q000737:chemistry*; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D004952:Esters; D010455:Peptides; D013438:Sulfhydryl Compounds; D006858:Hydrofluoric Acid
keywords: Boc chemistry; high-throughput synthesis; peptides; solid-phase synthesis; thioesters