Scalable synthesis and coupling of quaternary α-arylated amino acids: α-aryl substituents are tolerated in α-helical peptides

Daniel J Leonard; Francis Zieleniewski; Isabelle Wellhöfer; Emily G Baker; John W Ward; Derek N Woolfson; Jonathan Clayden

doi:10.1039/d1sc01378e

Scalable synthesis and coupling of quaternary α-arylated amino acids: α-aryl substituents are tolerated in α-helical peptides

Daniel J Leonard, Francis Zieleniewski, Isabelle Wellhöfer, Emily G Baker, John W Ward, Derek N Woolfson, Jonathan Clayden

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Abstract

Quaternary amino acids are important tools for the modification and stabilisation of peptide secondary structures. Here we describe a practical and scalable synthesis applicable to quaternary alpha-arylated amino acids (Q4As), and the development of solid-phase synthesis conditions for their incorporation into peptides. Monomeric and dimeric α-helical peptides are synthesised with varying degrees of Q4A substitution and their structures examined using biophysical methods. Both enantiomers of the Q4As are tolerated in folded monomeric and oligomeric α-helical peptides, with the (R)-enantiomer slightly more so than the (S).

Original language	English
Article number	9386
Pages (from-to)	9386-9390
Number of pages	5
Journal	Chemical Science
Volume	12
Issue number	27
Early online date	9 Jun 2021
DOIs	https://doi.org/10.1039/d1sc01378e https://doi.org/10.1039/d1sc01378e
Publication status	Published - 21 Jul 2021

Bibliographical note

Funding Information:
This work was supported by the EPSRC through the Bristol Chemical Synthesis Centre for Doctoral Training EP/G036764/1 (studentship to F. Z.) and programme grant EP/P027067 (awarded to JPC), A. P. Møller Lægefonden, Rudolph Als Fon-den, Oticon Fonden and Julie Von Müllens Fonden. DNW held a Royal Society Wolfson Research Merit Award (WM140008). We also thank the University of Bristol School of Chemistry Mass Spectrometry Facility for use of the EPSRC-funded Bruker Ultraex MALDI-TOF/TOF instrument (EP/K03927X/1), and the BBSRC/EPSRC-funded BrisSynBio (BB/L01386X1) for access to its peptide synthesisers.

Publisher Copyright:
© The Royal Society of Chemistry.

Research Groups and Themes

BCS and TECS CDTs
Bristol BioDesign Institute

Keywords

synthetic biology

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This is the final published version of the article (version of record). It first appeared online via Royal Society of Chemistry at https://pubs.rsc.org/en/content/articlelanding/2021/sc/d1sc01378e . Please refer to any applicable terms of use of the publisher.
Final published version, 792 KBLicence: CC BY
Full-text PDF (final published version)
This is the final published version of the article (version of record). It first appeared online via Royal Society of Chemistry at 10.1039/D1SC01378E. Please refer to any applicable terms of use of the publisher.
Final published version, 792 KBLicence: CC BY

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title = "Scalable synthesis and coupling of quaternary α-arylated amino acids: α-aryl substituents are tolerated in α-helical peptides",

abstract = "Quaternary amino acids are important tools for the modification and stabilisation of peptide secondary structures. Here we describe a practical and scalable synthesis applicable to quaternary alpha-arylated amino acids (Q4As), and the development of solid-phase synthesis conditions for their incorporation into peptides. Monomeric and dimeric α-helical peptides are synthesised with varying degrees of Q4A substitution and their structures examined using biophysical methods. Both enantiomers of the Q4As are tolerated in folded monomeric and oligomeric α-helical peptides, with the (R)-enantiomer slightly more so than the (S).",

keywords = "synthetic biology",

author = "Leonard, {Daniel J} and Francis Zieleniewski and Isabelle Wellh{\"o}fer and Baker, {Emily G} and Ward, {John W} and Woolfson, {Derek N} and Jonathan Clayden",

note = "Funding Information: This work was supported by the EPSRC through the Bristol Chemical Synthesis Centre for Doctoral Training EP/G036764/1 (studentship to F. Z.) and programme grant EP/P027067 (awarded to JPC), A. P. M{\o}ller L{\ae}gefonden, Rudolph Als Fon-den, Oticon Fonden and Julie Von M{\"u}llens Fonden. DNW held a Royal Society Wolfson Research Merit Award (WM140008). We also thank the University of Bristol School of Chemistry Mass Spectrometry Facility for use of the EPSRC-funded Bruker Ultraex MALDI-TOF/TOF instrument (EP/K03927X/1), and the BBSRC/EPSRC-funded BrisSynBio (BB/L01386X1) for access to its peptide synthesisers. Publisher Copyright: {\textcopyright} The Royal Society of Chemistry.",

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doi = "10.1039/d1sc01378e",

language = "English",

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T2 - α-aryl substituents are tolerated in α-helical peptides

AU - Leonard, Daniel J

AU - Zieleniewski, Francis

AU - Wellhöfer, Isabelle

AU - Baker, Emily G

AU - Ward, John W

AU - Woolfson, Derek N

AU - Clayden, Jonathan

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PY - 2021/7/21

Y1 - 2021/7/21

N2 - Quaternary amino acids are important tools for the modification and stabilisation of peptide secondary structures. Here we describe a practical and scalable synthesis applicable to quaternary alpha-arylated amino acids (Q4As), and the development of solid-phase synthesis conditions for their incorporation into peptides. Monomeric and dimeric α-helical peptides are synthesised with varying degrees of Q4A substitution and their structures examined using biophysical methods. Both enantiomers of the Q4As are tolerated in folded monomeric and oligomeric α-helical peptides, with the (R)-enantiomer slightly more so than the (S).

AB - Quaternary amino acids are important tools for the modification and stabilisation of peptide secondary structures. Here we describe a practical and scalable synthesis applicable to quaternary alpha-arylated amino acids (Q4As), and the development of solid-phase synthesis conditions for their incorporation into peptides. Monomeric and dimeric α-helical peptides are synthesised with varying degrees of Q4A substitution and their structures examined using biophysical methods. Both enantiomers of the Q4As are tolerated in folded monomeric and oligomeric α-helical peptides, with the (R)-enantiomer slightly more so than the (S).

KW - synthetic biology

U2 - 10.1039/d1sc01378e

DO - 10.1039/d1sc01378e

M3 - Article (Academic Journal)

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SN - 2041-6520

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EP - 9390

JO - Chemical Science

JF - Chemical Science

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M1 - 9386

ER -

Scalable synthesis and coupling of quaternary α-arylated amino acids: α-aryl substituents are tolerated in α-helical peptides

Abstract

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