Sequence-specific peptide synthesis by an artificial small-molecule machine

Bartosz Lewandowski; Guillaume De Bo; John W. Ward; Marcus Papmeyer; Sonja Kuschel; María J. Aldegunde; Philipp M.E. Gramlich; Dominik Heckmann; Stephen M. Goldup; Daniel M. D'Souza; Antony E. Fernandes; David A. Leigh

doi:10.1126/science.1229753

Sequence-specific peptide synthesis by an artificial small-molecule machine

Bartosz Lewandowski, Guillaume De Bo, John W. Ward, Marcus Papmeyer, Sonja Kuschel, María J. Aldegunde, Philipp M.E. Gramlich, Dominik Heckmann, Stephen M. Goldup, Daniel M. D'Souza, Antony E. Fernandes, David A. Leigh^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

542 Citations (Scopus)

Abstract

The ribosome builds proteins by joining together amino acids in an order determined by messenger RNA. Here, we report on the design, synthesis, and operation of an artificial small-molecule machine that travels along a molecular strand, picking up amino acids that block its path, to synthesize a peptide in a sequence-specific manner. The chemical structure is based on a rotaxane, a molecular ring threaded onto a molecular axle. The ring carries a thiolate group that iteratively removes amino acids in order from the strand and transfers them to a peptide-elongation site through native chemical ligation. The synthesis is demonstrated with ∼10¹⁸ molecular machines acting in parallel; this process generates milligram quantities of a peptide with a single sequence confirmed by tandem mass spectrometry.

Original language	English
Pages (from-to)	189-193
Number of pages	5
Journal	Science
Volume	339
Issue number	6116
DOIs	https://doi.org/10.1126/science.1229753
Publication status	Published - 11 Jan 2013

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title = "Sequence-specific peptide synthesis by an artificial small-molecule machine",

abstract = "The ribosome builds proteins by joining together amino acids in an order determined by messenger RNA. Here, we report on the design, synthesis, and operation of an artificial small-molecule machine that travels along a molecular strand, picking up amino acids that block its path, to synthesize a peptide in a sequence-specific manner. The chemical structure is based on a rotaxane, a molecular ring threaded onto a molecular axle. The ring carries a thiolate group that iteratively removes amino acids in order from the strand and transfers them to a peptide-elongation site through native chemical ligation. The synthesis is demonstrated with ∼1018 molecular machines acting in parallel; this process generates milligram quantities of a peptide with a single sequence confirmed by tandem mass spectrometry.",

author = "Bartosz Lewandowski and {De Bo}, Guillaume and Ward, {John W.} and Marcus Papmeyer and Sonja Kuschel and Aldegunde, {Mar{\'i}a J.} and Gramlich, {Philipp M.E.} and Dominik Heckmann and Goldup, {Stephen M.} and D'Souza, {Daniel M.} and Fernandes, {Antony E.} and Leigh, {David A.}",

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T1 - Sequence-specific peptide synthesis by an artificial small-molecule machine

AU - Lewandowski, Bartosz

AU - De Bo, Guillaume

AU - Ward, John W.

AU - Papmeyer, Marcus

AU - Kuschel, Sonja

AU - Aldegunde, María J.

AU - Gramlich, Philipp M.E.

AU - Heckmann, Dominik

AU - Goldup, Stephen M.

AU - D'Souza, Daniel M.

AU - Fernandes, Antony E.

AU - Leigh, David A.

PY - 2013/1/11

Y1 - 2013/1/11

N2 - The ribosome builds proteins by joining together amino acids in an order determined by messenger RNA. Here, we report on the design, synthesis, and operation of an artificial small-molecule machine that travels along a molecular strand, picking up amino acids that block its path, to synthesize a peptide in a sequence-specific manner. The chemical structure is based on a rotaxane, a molecular ring threaded onto a molecular axle. The ring carries a thiolate group that iteratively removes amino acids in order from the strand and transfers them to a peptide-elongation site through native chemical ligation. The synthesis is demonstrated with ∼1018 molecular machines acting in parallel; this process generates milligram quantities of a peptide with a single sequence confirmed by tandem mass spectrometry.

AB - The ribosome builds proteins by joining together amino acids in an order determined by messenger RNA. Here, we report on the design, synthesis, and operation of an artificial small-molecule machine that travels along a molecular strand, picking up amino acids that block its path, to synthesize a peptide in a sequence-specific manner. The chemical structure is based on a rotaxane, a molecular ring threaded onto a molecular axle. The ring carries a thiolate group that iteratively removes amino acids in order from the strand and transfers them to a peptide-elongation site through native chemical ligation. The synthesis is demonstrated with ∼1018 molecular machines acting in parallel; this process generates milligram quantities of a peptide with a single sequence confirmed by tandem mass spectrometry.

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Sequence-specific peptide synthesis by an artificial small-molecule machine

Abstract

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