The University of Adelaide
New Selenium-Mediated Methods for Protein Synthesis and Modification
EARLY CAREER LECTURESHIP AWARD I
Monday, June 26, 2023, at 08:55 am - 09:20 am
Selenium provides unique opportunities in the chemical synthesis and modification of proteins owing to its enhanced reactivity compared to corresponding sulfur-containing components. We have extended the application of such reactivity to expressed protein fragments through the conversion of C-terminal acyl hydrazides to the corresponding selenoesters which provide valuable intermediates for the synthesis of proteins with modifications near their C-terminus via the Diselenide-Selenoester Ligation, DSL.1
These selenoesters can also be used for the incorporation of diselenides into expressed proteins to serve as substrates for late-stage modification via Photocatalytic Diselenide Contraction, PDC.2 Taken together, these technologies allow us to access pure samples of homogenously modified proteins for downstream evaluation to elucidate the functional roles of natural and designer modifications, alike.
1. S. S. Kulkarni, E. E. Watson, J. W. C. Maxwell, G. Niederacher, J. Johansen-Leete, S. Huhmann, S. Mukherjee, A. R. Norman, J. Kriegesmann, C. F. W. Becker, and R. J. Payne. Expressed Protein Selenoester Ligation. Angew. Chem. Int. Ed. 2022, 61, 20, e202200163
2. L. J. Dowman, S. S. Kulkarni, J. V. Alegre-Requena, A. M. Giltrap, A. R. Norman, A. Sharma, L. C. Gallegos, A. S. Mackay, A. P. Welegedara, E. E. Watson, D. van Raad, G. Niederacher, S. Huhmann, N. Proschogo, K. Patel, M. Larance, C. F. W. Becker, J. P. Mackay, G. Lakhwani, T. Huber, R. S. Paton, and
R. J. Payne. Site-Selective Photocatalytic functionalization of peptides and proteins at Selenocysteine. Nat. Commun. 2022, 13, 6885
One of the fundamental principles of life is being able to sense and respond to changes in the environment. By developing smart drugs and therapeutic agents capable of this type of molecular logic we can help improve their selectivity, and therefore reduce toxicity. Such systems have three key components: the inputs, this is the part capable of binding to a target molecule or sensing a change, the outputs, this is the part that does something in response to this new information in essence release a drug, and the circuitry, this is the part that connects the inputs and the outputs, helping to transfer the information. Much like a computer, these components can be wired together to form a functional system, with the individual parts able to be swapped in and out in a modular manner to rapidly create new systems, capable of targeting new problems.
My research focuses on using biomolecules, peptides, proteins, nucleic acids, as the key components in such responsive systems. These systems are underpinned by a combination of organic synthesis, solid phase peptide and nucleic acid synthesis, photocatalysis and bioconjugation to create final functional systems.