Thesis

Profiling sulfur(VI) fluorides as tools for chemical biology

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2023
Thesis identifier
  • T17500
Person Identifier (Local)
  • 201976099
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Covalent inhibition has found extensive application in chemical biology, beyond direct application to drugs, to fragment screening and chemoproteomic approaches that enable the interrogation of protein targets. Established covalent strategies predominantly rely on the presence of a suitably positioned cysteine residue within the target protein, which are of low abundance across the proteome. Functionalities that can expand the scope of protein targets that can be covalently modified are therefore valuable. Sulfur(VI) fluorides (SVI-F) have emerged recently as functionalities that modify multiple nucleophilic amino acid residues and therefore target a broad scope of proteins. While SVI-Fs have demonstrated utility in numerous inhibitors and chemical biology workflows, these electrophiles have been applied with minimal rational design. An improved understanding of SVI-F reactivity is crucial for their optimal application in chemical biology. This thesis describes the profiling of a panel of SVI-Fs in the context of chemical biology applications. The profiling studies provided an in-depth understanding of the hydrolytic stability, amino acid reactivity, protein reactivity and chemoproteomic utility of SVI-F functionalities that are suitable for incorporation into chemical tools. The work demonstrated that SVI-Fs have diverse but tuneable intrinsic reactivity that is influenced by SVI-F electronics, buffer pH and buffer identity. A computational model was subsequently developed to predict SVI-F intrinsic reactivity, removing the requirement for iterative design-make-test cycles. The panel of SVI-Fs was then conjugated to fragment binders to provide tools for assessment of the reactivity of SVI-Fs towards proteins. It was found that SVI-F intrinsic reactivity did not always translate directly to protein reactivity, which was also influenced by the identity of the fragment. Similarly, the reversible affinities of the fragments were impacted by the identity of the SVI-F electrophile. Protein reactivity was also examined in the context of kinase modification using a panel of elaborated SVI-F kinase probes, which demonstrated that the use of a sufficiently high affinity probe can drive the modification of SVI-Fs that have low intrinsic reactivity. Chemoproteomic studies with the SVI-F probes revealed good coverage of the kinome and wider proteome, including diverse protein classes and many targets that have not been liganded to date. It was demonstrated that SVI-F electrophiles can capture an expanded range of proteins compared to established cysteine-targeting strategies, highlighting the opportunity for SVI-Fs to expand the liganded proteome.
Advisor / supervisor
  • Burley, Glenn A.
  • Bush, Jacob T.
Resource Type
Note
  • Previously held under moratorium in Chemistry department (GSK) from 5/9/23 until 12/9/25.
  • The confidentiality statement on each page of this thesis DOES NOT apply
DOI
Funder
Embargo Note
  • The digital version of this thesis is restricted to Strathclyde users only until 5th September 2028.

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