Adaptation of BODIPY dyes to investigate drug delivery and develop 'self-reporting' activity-based probes

O'Byrne, Sean (2018) Adaptation of BODIPY dyes to investigate drug delivery and develop 'self-reporting' activity-based probes. PhD thesis, University of Glasgow.

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The work presented within adapts BODIPY fluorescent dyes for two distinct purposes: to investigate drug delivery into parasites and to develop ‘self-reporting’ activity-based probes for protein profiling.

Methods for the treatment of parasitic diseases (human, animal and plant) have recently focussed on techniques for improving the delivery of a drug into the host infected cell, followed by its subsequent uptake into the parasite. In an effort to develop new anti-parasitic agents, a new system was developed, that is able to deliver low molecular weight units, as well as larger biomolecules (13 kD), selectively across cellular membranes. The delivery system can be selectively tuned depending on the type of parasite being targeted (i.e. kinetidoplastida, apicomplexan, worms).

Significantly, we have also been able to selectively target intracellular parasites without affecting uninfected host cells. This opens the tantalising opportunity to be able to use our system to deliver a variety of agents and vectors, with little or no toxicity, at all stages of the parasite’s life-cycle, including the intracellular stages.

The second theme of the thesis is activity-based probes. Activity-based probes are small molecule modifiers of proteins that help elucidate the roles of these proteins in both healthy and diseased cells. Kinase’s have a central role in cell signalling and disease, thus has been significant effort towards the development and application of chemical probes in this field. The activity-based probes developed are based on afatinib, an irreversible inhibitor of EGFR, an ErbB family kinase. Deregulation of ErbB kinases has been implicated in several cancers. Afatinib forms a conjugate with cysteine residue in the active site of these enzymes.

Probes have been prepared that incorporate functionalised BODIPY dyes. Upon reaction with thiols, the absorbance and emission profiles of the probes are modified. The probes are ‘self-reporting’ since formation of a covalent bond between the thiol and the probe can be monitored through absorbance or emission, allowing for easy detection.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Chemistry, drug delivery, parasites, BODIPY, EGFR, activity-based probes.
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Hartley, Prof. Richard
Date of Award: 2018
Embargo Date: 24 April 2021
Depositing User: Dr Sean O'Byrne
Unique ID: glathesis:2018-9035
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 01 May 2018 14:19
Last Modified: 23 May 2018 13:52

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