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Prebiotic Catalytic Peptide Ligation Yields Proteinogenic Peptides by Intramolecular Amide Catalyzed Hydrolysis Facilitating Regioselective Lysine Ligation in Neutral Water

Research output: Contribution to journalArticlepeer-review

Jyoti Singh, Daniel Whitaker, Benjamin Thoma, Saidul Islam, Callum S. Foden, Abil E. Aliev, Tom D. Sheppard, Matthew W. Powner

Original languageEnglish
Article number2c03486
Pages (from-to)10151-10155
Number of pages5
JournalJournal of the American Chemical Society
Issue number23
Published15 Jun 2022

Bibliographical note

Funding Information: We thank K. Karu (UCL Mass Spectrometry Facility). We thank the EPSRC (EP/K004980/1, EP/M507970/1, EP/P020410/1), Leverhulme Trust (RPG-2019-214), Simons Foundation (318881FY19), and Volkswagen Foundation (94743) for financial support. Publisher Copyright: © 2022 American Chemical Society. All rights reserved.


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    Uploaded date:01 Jun 2022

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King's Authors


The prebiotic origin of catalyst-controlled peptide synthesis is fundamental to understanding the emergence of life. Building on our recent discovery that thiols catalyze the ligation of amino acids, amides, and peptides with amidonitriles in neutral water, we demonstrate the outcome of ligation depends on pH and that high pK aprimary thiols are the ideal catalysts. While the most rapid thiol catalyzed peptide ligation occurs at pH 8.5-9, the most selective peptide ligation, that tolerates all proteinogenic side chains, occurs at pH 7. We have also identified the highly selective mechanism by which the intermediate peptidyl amidines undergo hydrolysis to α-peptides while demonstrating that the hydrolysis of amidines with nonproteinogenic structures, such as β- and γ-peptides, displays poor selectivity. Notably, this discovery enables the highly α-selective protecting-group-free ligation of lysine peptides at neutral pH while leaving the functional ϵ-amine side chain intact.

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