{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/388788"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/388788","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Hypervalent iodine reagents for protein functionalisation","abstract":"The efficacy of natural post-translational pathways in modifying specific amino acid residues has inspired the discovery of chemical methods that expand protein diversity and function. Methionine, a natural antioxidant in biological systems, provides a distinct handle for modification without compromising protein function. Methionine can be converted to diazo-sulfonium derivatives using hypervalent iodonium salts, producing versatile conjugates that can undergo further bioorthogonal modifications. This powerful strategy proceeds with high efficiency and chemoselectivity across a range of small proteins and polypeptides. In this work, we describe the development of a new generation of methionine-selective protein labelling reagents with improved reactivity and versatility, while enhancing the stability of the resultant protein conjugates. We have developed a new class of iodonium reagents wherein the ester motif is replaced with a ketone group. Our synthetic strategy tolerates the inclusion of a broad range of important functional groups, such as water-solubilising fragments and bioorthogonal handles, which can be incorporated via a modular approach. In a dipeptide model, we determined that our arylketone-bearing reagents exhibit enhanced reactivity and faster labelling kinetics compared to the original ester-bearing reagents. The advantages conferred by our improved suite of functionally diverse reagents have enabled us to develop faster, more selective, and more sensitive methods for protein functionalisation. Subsequently, we describe the N-arylation of hydroxylamine in peptide substrates using diaryliodonium salts in the presence of a base. This technique is rapid and tolerates water, but has only been demonstrated on small molecules. Here, we use N-arylation in conjunction with existing protein labelling techniques to demonstrate its effectiveness in a small peptide. This proves both its biorthogonality as well as its complementarity to alternative bioconjugation strategies.","abstract_html":"The efficacy of natural post-translational pathways in modifying specific amino acid residues has inspired the discovery of chemical methods that expand protein diversity and function. Methionine, a natural antioxidant in biological systems, provides a distinct handle for modification without compromising protein function. Methionine can be converted to diazo-sulfonium derivatives using hypervalent iodonium salts, producing versatile conjugates that can undergo further bioorthogonal modifications. This powerful strategy proceeds with high efficiency and chemoselectivity across a range of small proteins and polypeptides. In this work, we describe the development of a new generation of methionine-selective protein labelling reagents with improved reactivity and versatility, while enhancing the stability of the resultant protein conjugates. We have developed a new class of iodonium reagents wherein the ester motif is replaced with a ketone group. Our synthetic strategy tolerates the inclusion of a broad range of important functional groups, such as water-solubilising fragments and bioorthogonal handles, which can be incorporated via a modular approach. In a dipeptide model, we determined that our arylketone-bearing reagents exhibit enhanced reactivity and faster labelling kinetics compared to the original ester-bearing reagents. The advantages conferred by our improved suite of functionally diverse reagents have enabled us to develop faster, more selective, and more sensitive methods for protein functionalisation. Subsequently, we describe the N-arylation of hydroxylamine in peptide substrates using diaryliodonium salts in the presence of a base. This technique is rapid and tolerates water, but has only been demonstrated on small molecules. Here, we use N-arylation in conjunction with existing protein labelling techniques to demonstrate its effectiveness in a small peptide. This proves both its biorthogonality as well as its complementarity to alternative bioconjugation strategies.","abstract_has_math":false,"creators":["Goh, Zhang-He"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Gaunt, Matthew J"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-05-30","date_published":"2025-05-30","updated_at":"2026-07-22T22:24:16Z","subjects":["protein functionalisation","hypervalent iodine"],"languages":["eng"],"rights":[],"rights_urls":["https://www.repository.cam.ac.uk/bitstreams/7c1db836-cb3f-46df-b1b1-57d5591b8af0/download","http://purl.org/NET/rdflicense/allrightsreserved"],"identifier_entries":[{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000201481729"],"render_values":[{"text":"0000-0002-0148-1729","href":"https://orcid.org/0000-0002-0148-1729","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.120979","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Gaunt, Matthew J"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["The author is grateful to the Agency for Science, Technology and Research (A*STAR) Singapore for funding his PhD."]},{"key":"dc:creator","label":"Author","values":["Goh, Zhang-He"]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000201481729"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2025-05-30"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/388788"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["protein functionalisation","hypervalent iodine"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://www.repository.cam.ac.uk/bitstreams/7c1db836-cb3f-46df-b1b1-57d5591b8af0/download","http://purl.org/NET/rdflicense/allrightsreserved"]},{"key":"dc:rights.embargodate","label":"Dc Rights Embargodate","values":["2026-09-29"]},{"key":"dc:rights.embargotype","label":"Dc Rights Embargotype","values":["embargo"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.120979"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://www.repository.cam.ac.uk/bitstreams/692c85ca-7b39-4b53-a506-21039c1ee037/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The efficacy of natural post-translational pathways in modifying specific amino acid residues has inspired the discovery of chemical methods that expand protein diversity and function. 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In a dipeptide model, we determined that our arylketone-bearing reagents exhibit enhanced reactivity and faster labelling kinetics compared to the original ester-bearing reagents. The advantages conferred by our improved suite of functionally diverse reagents have enabled us to develop faster, more selective, and more sensitive methods for protein functionalisation. Subsequently, we describe the N-arylation of hydroxylamine in peptide substrates using diaryliodonium salts in the presence of a base. This technique is rapid and tolerates water, but has only been demonstrated on small molecules. Here, we use N-arylation in conjunction with existing protein labelling techniques to demonstrate its effectiveness in a small peptide. 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In a dipeptide model, we determined that our arylketone-bearing reagents exhibit enhanced reactivity and faster labelling kinetics compared to the original ester-bearing reagents. The advantages conferred by our improved suite of functionally diverse reagents have enabled us to develop faster, more selective, and more sensitive methods for protein functionalisation. Subsequently, we describe the N-arylation of hydroxylamine in peptide substrates using diaryliodonium salts in the presence of a base. This technique is rapid and tolerates water, but has only been demonstrated on small molecules. Here, we use N-arylation in conjunction with existing protein labelling techniques to demonstrate its effectiveness in a small peptide. 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