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Protein & Peptide Modification

Research in the laboratory in the field of protein modification focuses on deubiquitinating enzymes (DUBs), which are a key regulatory class of enzyme. There is growing evidence for a pivotal role of DUBs in pathologies including infection, autoimmunity, cancer and neurodegeneration. 

DUBs possess ubiquitin C-terminal hydrolytic activity and are responsible for removal of ubiquitin from its conjugates. Through the modification of ubiquitin, activity based probes resembling ubiquitin–substrate conjugates can be developed. Such probes are of great use in the investigation of DUBs and ubiquitin conjugation machinery. Modification techniques in this area range from protein expression and modification right through to purely synthetic approaches. 

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Our research also concentrates on the generation of modified peptides to inhibit protein-protein interactions (PPIs). PPIs are involved in a large number of biological processes including signal transduction and membrane transport. However, the majority of PPIs have large interaction surfaces and lack preformed and well-defined hydrophobic cavities. As such, small molecule ligands are unable to disrupt these interactions. Peptides offer an alternative to small molecules and have shown considerable promise in disruption of PPIs.

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Research in the laboratory focuses on the synthesis of unnatural amino acids and modified peptides to inhibit PPIs that occur in the nucleotide excision repair (NER) pathway. This pathway repairs DNA and is highly versatile. The upregulation of the NER pathway has been associated with chemotherapy resistance, and as such this pathway can be targeted for the development of novel cancer treatments.

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Relevant Publications

Calvert, S. H.; McGouran, J. F. Rapid Capture of Peptide Binders Nature Reviews Chemistry, 2023, doi: 10.1038/s41570-023-00517-7

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McKenna, S. M.; Fay, E. M.; McGouran, J. F. Flipping the switch: Innovations in inducible probes for protein profiling ACS Chem. Biol, 2021

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Taylor, N. C.; McGouran, J. F. Investigating eosin Y as a photocatalyst for the radical-dependent activity-based probing of deubiquitinating enzymes, Organic & Biomolecular Chemistry, 2021

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Taylor, N. C.; Hessman, G; Kramer, H; McGouran, J. F. Probing enzyme activity-a radical approach, Chemical Science, 202;0

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Taylor, N. C.; McGouran, J. F. Strategies to target specific components of the ubiquitin conjugation/deconjugation machinery, Frontiers in Chemistry, 2019,

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McGouran JF, Gaertner SR, Altun M, Kramer HB, Kessler BM, Deubiquitinating enzyme specificity for ubiquitin chain topology profiled by di-ubiquitin activity probes., Chemistry & biology, 20, (12), 2013, 1447-55

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