Traceless Chemoenzymatic Peptide Synthesis

AstraZeneca/EPSRC-funded Industrial Doctoral Landscape Award (fully-funded PhD project, UK students only due to funding restrictions)

Keywords: Synthetic Chemistry, Chemical Biology, Biocatalysis, Peptide Synthesis, Sustainable Chemistry

About the project

A 48-month PhD studentship funded by AstraZeneca and the EPSRC is available in the research group of Dr Nicholas Mitchell based in the School of Chemistry, University of Nottingham (https://nicholasjmitchell.wixsite.com/themitchellgroup).

Start date: 1 October 2025. Application deadline: 6 January 2025

Background

Solid-phase peptide synthesis (SPPS) is a Nobel prize-winning and highly effective technique that is applied globally to enable the routine synthesis of peptides. However, due to a reliance on toxic solvents, generation of high volumes of waste, and poor atom economy, this method is a long way from meeting the principles of green chemistry. The use of enzymes (biocatalysts) to form amide bonds between unprotected peptide fragments in aqueous solution represents a ‘green’ approach to peptide assembly.

Objectives

In collaboration with AstraZeneca, this PhD studentship will explore traceless chemoenzymatic peptide synthesis in aqueous or aqueous-organic solvent mixtures to enable a more sustainable process to be developed. Minimal, crude peptide fragments will be used directly with ligases derived from serine proteases to iteratively assemble these short peptides on a solid support. Throughout the studentship, bioinformatic and modelling tools will be applied to discover new ligases. Expression and evaluation of these novel enzymes will be followed by re-engineering to enhance stability, activity and tolerance to afford the next generation of ligases for chemoenzymatic peptide synthesis.

Training and environment

The PhD student will receive comprehensive training at the interface between synthetic chemistry and chemical biology, developing skills that will enable them to pursue a successful career in academia or industry. The project will be based in a state-of-the-art synthetic chemistry lab, equipped with two microwave-assisted peptide synthesisers, fully automated analytical and preparative HPLC, AKTA protein chromatography systems and facilities for protein expression. The student will also have full access to the School’s excellent technician-run analytical facilities which include a suite of mass spectrometers and NMR systems (including an 800 MHz NMR).

Recent and on-going projects in Dr Mitchell’s lab include the development of biocatalytic and electrochemical tools for the late-stage functionalisation of peptides, FeS-peptide clusters applied as redox mediators (ChemBioChem 2023, 24, e202300250), the preparation of peptide-oligonucleotide conjugates as cancer therapeutics, and the exploration of operationally simple photochemical methods to modify peptide and protein scaffolds (Angew. Chem. Int. Ed. 2020, 59, 23659-23667; Angew. Chem. Int. Ed. 2022, 61, e202110223; Chem. Eur. J. 2023, 29, e202202503; Org. Lett. 2023, 23, 5459-5464; Chem. Sci. 2024, 15, 9612-9619).

Impact

This project has the potential to deliver a step-change in the sustainable production of large peptides. The application of biocatalysts to the assembly of peptides using short, unprotected peptides in green solvents will dramatically reduce toxic solvent/chemical waste and represent a significantly more sustainable process compared to the current, globally applied, technology.

Entry requirements

Applications are invited from UK home students (due to funding restrictions) with an interest in synthetic chemistry, peptide chemistry, biocatalysis and chemical biology. Applicants should have, or expect to achieve, at least a 2:1 Honours Masters degree (or BSc with substantial research experience) in Chemistry, Natural Science, Molecular Biology or similar.

To apply please send a CV (max 2 pages) and a cover letter describing your motivation to study for a PhD in this field to [Email Address Removed]