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

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

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)
46 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article number2c03486
Pages (from-to)10151-10155
Number of pages5
JournalJournal of the American Chemical Society
Volume144
Issue number23
Early online date31 May 2022
DOIs
Publication statusPublished - 15 Jun 2022

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