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Mitchell, Nicholas

Nicholas Mitchell

University of Nottingham

Talk Title

A Radical Approach to the Site-Selective Modification of Peptides and Proteins

Presentation Time

Wednesday, June 28, 2023, at 09:20 am - 09:40 am

The diverse array of chemical functionality displayed by the 20 canonical amino acids presents both challenges and opportunities for the site-selective modification of peptides and proteins. An extensive range of reactions have been reported to modify the majority of the proteinogenic residues, providing tools to enable the study and manipulation of biological systems, and the preparation of therapeutic/diagnostic agents.1 To be effective, bioconjugation techniques must be rapid, high-yielding under mild conditions, and chemoselective. Owing to the superior nucleophilicity of the thiol group of cysteine, Cys, and its relatively low abundance across eukaryotic proteomes, circa 2%, many reported techniques target this residue to selectively install groups of interest.

abstract image

Site-selective installation of Nε-modified sidechains (Lys PTMs) via visible-light-mediated desulfurative C-C bond formation.2

To further contribute to this synthetic tool kit, we are exploring the site-selective modification of peptides and proteins via interception of free-radical-mediated desulfurization. By exploiting the homolytic lability of the C-S bond of Cys, we have developed a visible-light-mediated desulfurative C(sp3)–C(sp3) bond forming reaction that enables the site-selective installation of Nε-modified sidechains into peptides and proteins of interest, see figure.2 Rapid, operationally simple, and tolerant to ambient atmosphere, we demonstrate the installation of a range of lysine, Lys, post-translational modifications, PTMs, and PTM mimics3 into model peptides and proteins.

Furthermore, by utilizing persistent radical traps, we have developed a broadly applicable bioconjugation technique to install groups of interest via formation of an amino-oxy linkage.4 The reaction is rapid, high yielding and chemoselective; the resulting bioconjugate is stable at varying pH and high temperature, and selectively cleavable under mildly acidic conditions with the addition of a low oxidation state transition metal. This method translates well onto larger and more complex peptides and proteins carrying a wealth of chemical diversity.


1. Omar Boutureira and Gonçalo J. L. Bernardes. Advances in Chemical Protein Modification. Chem. Rev. 2015, 115, 2174-2195

2. Rhys C. Griffiths, Frances R. Smith, Jed E. Long, Daniel Scott, Huw E. L. Williams, Neil J. Oldham, Robert Layfield, Nicholas J. Mitchell. Site-Selective Installation of Nε-Modified Sidechains into Peptide and Protein Scaffolds via Visible-Light-Mediated Desulfurative C–C Bond Formation. Angew. Chem. Int. Ed. 2022, 61, e202110223

3. Rhys C. Griffiths, Frances R. Smith, Diyuan Li, Jasmine Wyatt, David M. Rogers, Jed E. Long, Lola M. L. Cusin, Patrick J. Tighe, Robert Layfield, Jonathan D. Hirst, Manuel M. Müller, Nicholas J. Mitchell. Cysteine-Selective Modification of Peptides and Proteins via Desulfurative C−C Bond Formation. Chem. Eur. J. 2023, DOI: 10.1002/chem.202202503

4. Rhys C. Griffiths, Frances R. Smith, Jed E. Long, Huw E. L. Williams, Robert Layfield, Nicholas J. Mitchell. Site-Selective Modification of Peptides and Proteins via Interception of Free-Radical-Mediated Dechalcogenation. Angew. Chem. Int. Ed. 2020, 59, 23659-23667

Nick received an MChem degree from the University of Southampton in 2004, before joining Prof. Stefan Howorka's group at UCL to investigate the chemical modification of oligonucleotides in 2005. He was awarded a Graduate Research Scholarship in 2008 and received his Ph.D. in 2009. Nick remained at UCL as a PDRA under the joint supervision of Prof. Alethea Tabor and Prof. Helen Hailes to work on MRI and SPECT imaging of liposomal drug delivery. In 2013 he moved to Prof. Richard Payne's lab at the University of Sydney to develop novel peptide ligation methodologies. Nick took up a Nottingham Research Fellowship, based in the School of Chemistry, in October 2016, and was promoted to Assistant Professor of Biological Chemistry in 2019.

Nicholas Mitchell
Nicholas Mitchell, talk image 1
Nicholas Mitchell, talk image 2
Nicholas Mitchell, talk image 3
Nicholas Mitchell, talk image 4