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Prebiotic peptide elongation by the chemoselective ligation of aminonitriles

Canavelli, Pierre; (2020) Prebiotic peptide elongation by the chemoselective ligation of aminonitriles. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

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.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Prebiotic peptide elongation by the chemoselective ligation of aminonitriles
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10090465
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