Barat, Abid; (2025) On the Spontaneous Formation of Peptides and the Aetiology of Proline Peptides. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In extant biochemistry, peptide synthesis is orchestrated by a complex suite of enzymes, which are themselves a product of evolution. The fundamental nature of life’s exploitation of peptides suggests they must have played a vital role during the onset of life; thus, their chemoselective aqueous synthesis is a key target for prebiotic chemistry. The prebiotic protecting group-free synthesis of peptides from amino acids yields peptides extremely inefficiently. However, thiols catalyse the α-selective peptide ligation of prebiotically plausible peptide-nitriles in water, neatly bypassing this issue. Here, initially, we demonstrate that cysteamine and cystamine can participate in Strecker chemistry, considered to be the foremost pathway to prebiotic amino acid and their peptides synthesis, to furnish N-thioethyl-aminonitriles (and N-thioethyl-amino acids), which are predisposed to undergo spontaneous, α-selective peptide-nitrile ligation via intramolecular thiol-catalysis. Our findings suggest that the cysteamine moiety may have played an effective role in selective chemical ligation of prebiotic peptoids and peptides. It is of note that cysteamine constitutes the crucial functional fragment of the universal cofactor, coenzyme A (CoA), which plays a pivotal role in contemporary metabolism, particularly in non-ribosomal peptide synthesis. Hence, the intriguing possibility arises that cysteamine might have been intricately linked to peptide synthesis at the origins of life. Secondly, recognising that proline is an odd amino acid, consisting of N-alkylated structure that is then connected to its R-group via a pyrrolidine ring, we questioned if there is special chemistry that selects proline as the only N-alkylated amino acid. To this end, we initially demonstrate that proline and pipecolic acid are both accessible through Strecker chemistry, but not its 4-membered homologue (2-carboxy azetidine). We then demonstrate that α-functionalised pyrrolidine nucleophiles undergo amide bond formation (quantitative yield) in water but not α-functionalised piperidine; therefore, quantitatively differentiating between the prebiotically plausible proline and pipecolic acid. Additionally, we demonstrate non-N-capped N-alkyl peptides undergo degradation to diketopiperazine (DKP) to furnish activating agent free amide bonds in water, but this is surprisingly suppressed if proline is employed.

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