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Title: Prebiotic peptide elongation by the chemoselective ligation of aminonitriles
Author: Canavelli, Pierre
ISNI:       0000 0004 8506 6702
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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Elucidating the sequence of events that led to the emergence of life on Earth remains one of the most fundamental open problems in all of science. At its core, a living system requires a substrate able to store, replicate and modify information. Due to its ability to serve both as a genetic information carrier and biocatalyst, RNA was first proposed to be sufficient. However, decades of efforts have failed to overcome the difficulties met when attempting to experimentally realise pure RNA models. A recent development was the proposal of a hybrid peptide-RNA world, which would tap into the enzymatic and structural capacity of peptides to complement the properties of RNA. While promising, this hypothesis found itself limited by similar hurdles. Chiefly, the formation of peptide bonds under prebiotic conditions remains a daunting challenge. Although amides are arguably the most important chemical group in all of biology and synthetic chemistry, their formation remains infamously difficult. These difficulties are compounded by the specificities of the prebiotic environment, which mandates that amidations happen in water, and precludes the use of sophisticated synthetic reagents. Due to its biomimetic nature and the assumed prebiotic abundance of amino acid monomers, the field has traditionally focused on the free polymerisation of amino acids. However, all documented amino acid-based strategies have failed to produce sufficient amounts of peptides, and are limited to a small subset of the proteinogenic amino acids. This work marks a clear departure from such paradigms, and sets out to explore the reactivity of aminonitrile precursors to amino acids. Herein, we demonstrate that (i) aminonitriles can be converted to N-capped peptide thioacids and aminothioacids; (ii) those thioacids chemoselectively ligate with aminonitriles to afford proteinogenic structures; (iii) this methodology can operate as a continuous, one-pot elongation cycle, which affords N-capped peptides in unprecedentedly high yields. Those findings bring to light a direct link between prebiotic protometabolism and the canonical peptide structures of extant biology, and pave the way towards the experimental realisation of hybrid protein-RNA protobiological systems.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available