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Electrochemical Modification of Polypeptides at Selenocysteine |
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| Authors: | Angus S. Mackay Joshua W. C. Maxwell Max J. Bedding Dr. Sameer S. Kulkarni Dr. Stephen A. Byrne Lucas Kambanis Dr. Mihai V. Popescu Prof. Robert S. Paton Assoc. Prof. Lara R. Malins Dr. Anneliese S. Ashhurst Dr. Leo Corcilius Prof. Richard J. Payne |
| Affiliation: | 1. School of Chemistry, The University of Sydney, Sydney, NSW 2006 Australia;2. School of Chemistry, The University of Sydney, Sydney, NSW 2006 Australia Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney, NSW 2006 Australia;3. Department of Chemistry, Colorado State University, Fort Collins, CO 80523 USA;4. Research School of Chemistry, Australian National University, Canberra, ACT 2601 Australia Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University, Canberra, ACT 2601 Australia;5. School of Chemistry, The University of Sydney, Sydney, NSW 2006 Australia School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006 Australia |
| Abstract: | Mild strategies for the selective modification of peptides and proteins are in demand for applications in therapeutic peptide and protein discovery, and in the study of fundamental biomolecular processes. Herein, we describe the development of an electrochemical selenoetherification (e-SE) platform for the efficient site-selective functionalization of polypeptides. This methodology utilizes the unique reactivity of the 21st amino acid, selenocysteine, to effect formation of valuable bioconjugates through stable selenoether linkages under mild electrochemical conditions. The power of e-SE is highlighted through late-stage C-terminal modification of the FDA-approved cancer drug leuprolide and assembly of a library of anti-HER2 affibody conjugates bearing complex cargoes. Following assembly by e-SE, the utility of functionalized affibodies for in vitro imaging and targeting of HER2 positive breast and lung cancer cell lines is also demonstrated. |
| Keywords: | Electrochemistry Peptides Proteins Selenocysteine Selenoethers |