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High‐Throughput Synthesis of Peptide α‐Thioesters: A Safety Catch Linker Approach Enabling Parallel Hydrogen Fluoride Cleavage
Author(s) -
Brust Andreas,
Schroeder Christina I.,
Alewood Paul F.
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300524
Subject(s) - native chemical ligation , thioester , linker , peptide , chemistry , combinatorial chemistry , cyclic peptide , cysteine , ethylene glycol , chemical ligation , peptide synthesis , biomolecule , chemical synthesis , biochemistry , organic chemistry , enzyme , computer science , in vitro , operating system
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.