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Novel approaches to site-selective protein modification using next-generation maleimides

Wall, Archie; (2021) Novel approaches to site-selective protein modification using next-generation maleimides. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Covalent amino acid modification is of significant interest to the scientific community. Its applications are immensely broad, spanning across therapeutics, diagnostics, materials science and beyond. Novel strategies to modify native proteins and peptides in a simple and efficient manner are highly valuable to researchers. As with the precision required in the design of small molecule drugs, researchers are determined to produce bioconjugates that are well defined, with high reproducibility and batch to batch consistency. One approach to achieve this is through careful modification of cysteine residues, which is typically carried out using well understood maleimide chemistry. In recent years, thiol-selective maleimide reactivity has been leveraged to create a series of next-generation maleimides (NGMs). This novel class of reagents exhibit the benefits of classical maleimides, but with improved tunability and stability. The work described in this thesis aimed to expand the applicability of the NGM platform, and demonstrate its versatility. These explorations first led to the generation of a platform to enable rapid, facile conjugation of payloads to human serum albumin (HSA). Secondly, investigation of fundamental NGM reactivity uncovered novel chemical methodology; a route that affords fast, dual modification with high stability, at a single cysteine site.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Novel approaches to site-selective protein modification using next-generation maleimides
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10126964
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