A straightforward method for automated Fmoc-based synthesis of bio-inspired peptide crypto-thioesters

Abstract : Despite recent advances, the direct Fmoc-based solid phase synthesis of peptide [small alpha]-thioesters for the convergent synthesis of proteins via native chemical ligation (NCL) remains a challenge in the field. We herein report a simple and general methodology, enabling access to peptide thioester surrogates. A novel C-terminal N-(2-hydroxybenzyl)cysteine thioesterification device based on an amide-to-thioester rearrangement was developed, and the resulting peptide crypto-thioesters can be directly used in NCL reactions with fast N [rightward arrow] S shift kinetics at neutral pH. These fast kinetics arise from our bio-inspired design, via intein-like intramolecular catalysis. Due to a well-positioned phenol moiety, an impressive >50 fold increase in the kinetic rate is observed compared to an O-methylated derivative. Importantly, the synthesis of this new device can be fully automated using inexpensive commercially available materials and does not require any post-synthetic steps prior to NCL. We successfully applied this new method to the synthesis of two long naturally-occurring cysteine-rich peptide sequences.
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Submitted on : Friday, December 2, 2016 - 3:04:27 PM
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Victor P. Terrier, Hélène Adihou, Mathieu Arnould, Agnès F. Delmas, Vincent Aucagne. A straightforward method for automated Fmoc-based synthesis of bio-inspired peptide crypto-thioesters. Chemical Science , The Royal Society of Chemistry, 2016, 7 (1), pp.339 - 345. ⟨10.1039/C5SC02630J⟩. ⟨hal-01407765⟩



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