eprintid: 10184728
rev_number: 12
eprint_status: archive
userid: 699
dir: disk0/10/18/47/28
datestamp: 2024-02-29 10:12:48
lastmod: 2024-02-29 10:12:48
status_changed: 2024-02-29 10:12:48
type: thesis
metadata_visibility: show
sword_depositor: 699
creators_name: Rochet, Léa Nicole Christiane
title: Exploiting the pyridazinedione scaffold to create novel bioconjugates, especially in the areas of reversible thiol modification and chemically constructed bispecifics
ispublished: unpub
divisions: UCL
divisions: B04
divisions: C06
divisions: F56
note: Copyright © The Author 2022. 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.
abstract: Over the past decades, the development of protein modification through cysteines, due their low abundance and high nucleophilicity, has enabled many advances in medicinal, imaging or diagnostics fields. In particular, their modification is of high interest for proteomic purposes, to inhibit the function of some proteins, or for the incorporation of any payload into a protein. 
On one hand, the development of probes/drugs for the targeting of cysteines in vivo has been clouded by their side, cytotoxic, effects. To overcome this, tools for the reversible modification of cysteines have been investigated. However, only a limited number of reagents have been reported so far and most of them suffer from stability issues, a lack of modularity and/or poor tunability. In this work, a library of tuneable nonbromo pyridazinediones (nonBr PD), as Michael acceptors, has been developed for their ability to react reversibly with cysteines. A correlation between the electrophilicity of the PDs and the Michael-addition/retro-Michael reaction rates was found. Those rates were reproducible onto a range of different cysteines, and the use of PD was exemplified on proteins/materials. Further investigations to understand the reactivity of those reagents led to the development of novel, improved, disulfide rebridging reagents. 
On the other hand, the focus has been on the development of chemical strategies for the stable modification of cysteine residues, applied to the generation of novel therapeutics, such as Antibody-Drug Conjugates (ADC) or bispecific formats for the treatment of cancer. Dibromo pyridazinediones (diBr PDs) scaffold have been previously reported for the homogeneous modification of disulfide bonds. Building on the works developed with diBr PDs and in collaboration with Wageningen University of Research and Queen’s University of Belfast, two novel bispecific formats based on site-selective modification strategies were developed and one of them was successfully tested in cell-based bioassays as a T-cell engager bispecific.
date: 2024-01-28
date_type: published
oa_status: green
full_text_type: other
thesis_class: doctoral_open
thesis_award: Ph.D
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 2136988
lyricists_name: Rochet, Léa
lyricists_id: LROCH43
actors_name: Rochet, Léa
actors_id: LROCH43
actors_role: owner
full_text_status: public
pages: 549
institution: UCL (University College London)
department: Chemistry
thesis_type: Doctoral
citation:        Rochet, Léa Nicole Christiane;      (2024)    Exploiting the pyridazinedione scaffold to create novel bioconjugates, especially in the areas of reversible thiol modification and chemically constructed bispecifics.                   Doctoral thesis  (Ph.D), UCL (University College London).     Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10184728/2/Thesis_Lea_Rochet_deposit.pdf