Nitriles: from prebiotic peptides to synthetic applications.

Widely accepted evidence exists for life in 3.5-3.4 billion year old sedimentary rocks, and there are indications life was already established on Earth 3.7 billion years ago. Approximately 3.9 billion years ago the Earth was subjected to intense meteoritic and cometary bombardment, and the largest impacts likely sterilised the Earth's surface. Life started after the last planet sterilising impact, but how? This is the ultimate question for those seeking to elucidate the origins of life, and one of the most profound and existential questions in science. The goal for those investigating the origins of life is to demonstrate, by experimentation, that life can emerge purely as a consequence of the rules of chemistry. Although this goal has been pursued for many years, and some major advances have been made, problems still remain that must be solved.

Recently, the development of "systems chemistry" has reinvigorated origins of life research, and renewed experimental assault. Based upon our own work, and key ideas and results from other researchers, colleagues and collaborators, an overarching scheme for the origin of life has been developed, in which the reactivity of nitriles (cyanides) and sulfides chaperoned and controlled the selective synthesis of life's essential molecules in the cradle of life. The scheme is made possible by the privileged reactivity of sulfides and nitriles. In this proposal we will develop this cyanosulfidic model further. We will elucidate how nitrile chemistry unites life's serine family of proteinogenic amino acids with a universally conserved enzyme cofactor, as well as providing access to extended peptides via ligation of nitriles in water.

Uniquely, this project will involve the application of plausible prebiotic chemical reactions to modern synthetic applications, including new strategies for the synthesis and semi-synthesis of amidines, amides, peptides and proteins. We will develop synthetic applications of the privileged reactions of the cyanosulfidic scenario, specifically Catalytic Peptide Ligation (CPL), which we recently elucidated in pursuit of the chemical origins of life. This reaction has considerable potential as a novel chemical tool for catalytic synthesis of peptides and amides. Amide and peptide bond formation is one of the most-important reactions in chemistry and biology, with 'amide formation avoiding poor atom economy reagents' identified by the ACS Green Chemical Institute as the top challenge for organic chemistry. Building on our published work, we will develop a catalytic strategy for amide and peptide ligation. New methodologies that exploit (solvent) water will be essential to the wider implementation of green chemistry strategies and the UK's green economy, and the small organic molecule catalysts we will develop are well-suited as artificial catalysts in comparison to enzymes and inorganic catalysts; they are simpler, typically non-toxic, and readily accessible.

The currently used approach to the semi-synthesis of extended peptides and proteins, native chemical ligation, has considerable limitations in terms of the nature of the amide bond that can be formed and its requirement for inherently unstable thioester starting materials. CPL offers untapped potential to circumvent these limitations, providing a powerful tool for preparation of synthetic peptides and amides. It requires no activating agents - the activation required to form an amide is built into the kinetically stable nitrile substrate. Additionally, we will develop new routes to the key substrates for CPL, i.e. peptide- and amido-nitriles, which are high value targets themselves (examples include: Saxagliptin, Vildagliptin, Paxlovid).