Poster Presentation 9th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2023

Late-stage Modification of Selenopeptides Using Electrochemical Selenoetherification (99460)

Sameer Kulkarni 1 2 , Angus Mackay 1 2 , Joshua Maxwell 1 2 , Max Bedding 1 2 , Stephen Byrne 1 2 , Lucas Kambanis 1 2 , Lara Malins 2 3 4 , Anneliese Ashhurst 1 5 , Leo Corcilius 1 2 , Richard J. Payne 1 2
  1. The University of Sydney, Sydney, NSW, Australia
  2. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney, NSW, Australia
  3. Research School of Chemistry, Australian National University, Canberra, ACT, Australia
  4. Research School of Chemistry, Australian National University, Canberra, ACT, Australia
  5. School of Medical Sciences, The University of Sydney, Sydney, NSW, Australia

While it is well-established that post-translational modifications (PTMs) play a vital role in modulating the structure and/or function of peptides and proteins, lack of tools to access site-selectively modified peptides and proteins bearing PTMs or designer modifications has hampered the progress towards identifying their specific role. As a result, various synthetic/semi-synthetic approaches have been developed, offering exquisite control over the site and type of modification to be incorporated.2-4 Particularly, late-stage modification of peptides offers exciting avenues to access therapeutic peptides with improved activity/stability. Although majority of such bio-conjugation methods rely on functionalization via Cys or Lys residues, these approaches lack regioselectivity, due to the occurrence of these amino acids at multiple positions within a protein.5,6 To circumvent these limitations, we have developed a novel electrochemical method, dubbed the electrochemical selenoetherification (e-SE), enabling chemo and regio-selective functionalization at selenocysteine, providing rapid access to site-selectively modified selenopeptides bearing a stable selenoether linkage.7 In this presentation, the power and utility of this method will be showcased through site-selective modification of Gonadotropin-releasing hormone (GnRH) analogue, Leuprolide and the zHER affibody to introduce a wide range of functionalities, including drugs, fluorophores, purification handles and DOTA ligands for theranostic applications.

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