A Radical Approach to the Site-Selective Modification of Peptides and Proteins — ASN Events
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  2. SESSION 3: Peptide and protein modifications
  3. A Radical Approach to the Site-Selective Modification of Peptides and Proteins

A Radical Approach to the Site-Selective Modification of Peptides and Proteins (#13)

Nicholas J. Mitchell 1 , Rhys C. Griffiths 2 , Frances R. Smith 3 , Diyuan Li 4 , Joanna C. Lee 5
  1. School of Chemistry, University of Nottingham, Nottingham, Nottinghamshire, United Kingdom
  2. School of Chemistry, University of Nottingham, Nottingham, Nottinghamshire, United Kingdom
  3. School of Chemistry, University of Nottingham, Nottingham, Nottinghamshire, United Kingdom
  4. School of Chemistry, University of Nottingham, Nottingham, Nottinghamshire, United Kingdom
  5. School of Chemistry, University of Nottingham, Nottingham, Nottinghamshire, United Kingdom

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. To be effective, bioconjugation techniques must be rapid, operationally simple, 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 (ca. 2%), many reported techniques target this residue to selectively install groups of interest. To contribute to the bioconjugate chemistry tool kit, we are exploring the site-selective modification of peptides and proteins via interception of free-radical-mediated desulfurisation.

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 permits the site-selective installation of modified sidechains into peptides and proteins.[1] Rapid, operationally simple and tolerant to ambient atmosphere, our chemistry enables the incorporation of a range of lysine (Lys) post-translational modifications (PTMs), and PTM mimics[2] into model peptides and proteins, and facilitates effective peptide cyclisation. Furthermore, by employing persistent radical traps, we have developed a broadly applicable protein bioconjugation technique to install groups of interest via formation of an amino-oxy linkage.[3] In addition to Cys-selective chemistry, we are also investigating the photocatalytic C2-alkylation of tryptophan (Trp) using bromodifluoroacetate/acetamide radical precursors.[4]

 

  1. R. C. Griffiths, F. R. Smith, J. E. Long, D. Scott, H. E. L. Williams, N. J. Oldham, R. Layfield, N. J. Mitchell, Angew. Chem. Int. Ed. 2022, 61, e202110223
  2. R. C. Griffiths, F. R. Smith, D. Li, J. Wyatt, D. M. Rogers, J. E. Long, L. M. L. Cusin, P. J. Tighe, R. Layfield, J. D. Hirst, M. M. Muller, N. J. Mitchell, Chem. Eur. J. 2023, 29, e202202503
  3. R. C. Griffiths, F. R. Smith, J. E. Long, H. E. L. Williams, R. Layfield, N. J. Mitchell, Angew. Chem. Int. Ed. 2020, 59, 23659-23667
  4. J. C. Lee, J. D. Cuthbertson, N. J. Mitchell, Org. Lett. 2023, DOI: 10.1021/acs.orglett.3c01795
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