Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.695337
Title: The design, synthesis and evaluation of novel inhibitors and activity-based probes targeting serine proteases in cystic fibrosis
Author: Ferguson, Timothy Edward Gordon
ISNI:       0000 0004 5995 0211
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2015
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Abstract:
Cystic Fibrosis (CF) is a genetic disorder primarily characterised by chronic infection and inflammation within the lungs. Serine proteases, in particular trypsin-Ilke serine proteases are associated with dehydration of the airways through proteolytiC activation of the Epithelial Sodium Channel (ENaC), leading to a reduction in mucociliary clearance and colonisation of the airways. The development of novel inhibitors and activity-based probes (ABPs) targeting these proteases was hypothesised as potential therapeutic agents and research tools to allow further insights into the disease mechanism. Novel decarboxylated substrate mimetics were designed and synthesised as potential reversible inhibitors of these Channel Activating Proteases (CAPs). This led to the development of a 4-amidinobenzylamine based compound which exhibited selective inhibition of matriptase and trypsin whilst displaying limited effects on other CAPs. An additional approach undertaken was the screen of a fragment library, previously identified through virtual screening as potential inhibitors of prostasin. This approach identified a 2,4-diamino-1,3,5-triazine analogue as a potential lead compound for the development of novel prostasin inhibitors. In the development of novel chemical tools for the detection and characterisation of novel CAPs, a library of broad-spectrum probes featuring a diphenyl ɑ-aminoalkylphosphonate moiety was synthesised. These compounds displayed potent irreversible inhibition with limited cross-reactivity and enabled successful detection of serine proteases utilising 'click-chemistry' techniques. In addition to the application of diphenyl ɑ-aminoalkylphosphonate ABPs, a novel class of irreversible protease inhibitor utilising N-alkyl glycine residues was developed. Consequently, a range of irreversible serine protease inhibitors and activity-based probes were synthesised displaying both broad-spectrum and more specific inhibitory properties. Promisingly, such compounds have displayed similar or improved inhibitory potency in comparison to their diphenyl ɑ-aminoalkylphosphonate counterparts. These compounds have also been applied successfully within Activity-Based ELlSA systems for the quantification of active serine protease. In conclusion, the development of these novel ABPs will aid future research into the proteolytic activation of ENaC and furthermore will allow insight into protease involvement within other disease states and may enable the quantification of protease biomarkers for use within both research and the clinic.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.695337  DOI: Not available
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