Site-selective photocatalytic functionalization of peptides and proteins at selenocysteine

Luke J Dowman; Sameer S Kulkarni; Juan V Alegre-Requena; Andrew M Giltrap; Alexander R Norman; Ashish Sharma; Liliana C Gallegos; Angus S Mackay; Adarshi P Welegedara; Emma E Watson; Damian van Raad; Gerhard Niederacher; Susanne Huhmann; Nicholas Proschogo; Karishma Patel; Mark Larance; Christian F W Becker; Joel P Mackay; Girish Lakhwani; Thomas Huber; Robert S Paton; Richard J Payne

doi:10.1038/s41467-022-34530-z

Site-selective photocatalytic functionalization of peptides and proteins at selenocysteine

Nat Commun. 2022 Nov 12;13(1):6885. doi: 10.1038/s41467-022-34530-z.

Authors

Luke J Dowman^{1

2}, Sameer S Kulkarni^{1

2}, Juan V Alegre-Requena³, Andrew M Giltrap^{1

2}, Alexander R Norman^{1

2}, Ashish Sharma^{1

4}, Liliana C Gallegos³, Angus S Mackay^{1

2}, Adarshi P Welegedara⁵, Emma E Watson^{1

2}, Damian van Raad⁵, Gerhard Niederacher⁶, Susanne Huhmann⁶, Nicholas Proschogo¹, Karishma Patel⁷, Mark Larance⁸, Christian F W Becker⁶, Joel P Mackay⁷, Girish Lakhwani^{1

4}, Thomas Huber⁵, Robert S Paton³, Richard J Payne^{9

10}

Affiliations

¹ School of Chemistry, The University of Sydney, Sydney, NSW, 2006, Australia.
² 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, 80523-1872, USA.
⁴ Australian Research Council Centre of Excellence in Exciton Science, The University of Sydney, Sydney, NSW, 2006, Australia.
⁵ Research School of Chemistry, Australian National University, Canberra, ACT, 2601, Australia.
⁶ Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
⁷ School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, 2006, Australia.
⁸ Charles Perkins Centre and School of Medical Sciences, The University of Sydney, Sydney, NSW, 2006, Australia.
⁹ School of Chemistry, The University of Sydney, Sydney, NSW, 2006, Australia. richard.payne@sydney.edu.au.
¹⁰ Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney, NSW, 2006, Australia. richard.payne@sydney.edu.au.

Abstract

The importance of modified peptides and proteins for applications in drug discovery, and for illuminating biological processes at the molecular level, is fueling a demand for efficient methods that facilitate the precise modification of these biomolecules. Herein, we describe the development of a photocatalytic method for the rapid and efficient dimerization and site-specific functionalization of peptide and protein diselenides. This methodology, dubbed the photocatalytic diselenide contraction, involves irradiation at 450 nm in the presence of an iridium photocatalyst and a phosphine and results in rapid and clean conversion of diselenides to reductively stable selenoethers. A mechanism for this photocatalytic transformation is proposed, which is supported by photoluminescence spectroscopy and density functional theory calculations. The utility of the photocatalytic diselenide contraction transformation is highlighted through the dimerization of selenopeptides, and by the generation of two families of protein conjugates via the site-selective modification of calmodulin containing the 21^st amino acid selenocysteine, and the C-terminal modification of a ubiquitin diselenide.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids
Peptides* / chemistry
Proteins
Selenocysteine* / chemistry

Substances

Selenocysteine
Peptides
Proteins
Amino Acids