Singh, Jyoti; Whitaker, Daniel; Thoma, Benjamin; Islam, Saidul; Foden, Callum S; Aliev, Abil E; Sheppard, Tom D; Singh, Jyoti; Whitaker, Daniel; Thoma, Benjamin; Islam, Saidul; Foden, Callum S; Aliev, Abil E; Sheppard, Tom D; Powner, Matthew W; - view fewer (2022) Prebiotic Catalytic Peptide Ligation Yields Proteinogenic Peptides by Intramolecular Amide Catalyzed Hydrolysis Facilitating Regioselective Lysine Ligation in Neutral Water. Journal of the American Chemical Society 10.1021/jacs.2c03486. (In press).

Preview

Text jacs.2c03486.pdf - Published Version Download (888kB) | Preview

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 pKa primary 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.

Download activity - last month

Export as XMLCSVJSON

Download activity - last 12 months

Export as JSONCSVXML

Downloads by country - last 12 months

Export as CSVXMLJSON

Archive Staff Only

View Item