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Title: Small molecule inhibitors and substrate analyses of protein arginine methyltransferases
Author: Varney, Amy
ISNI:       0000 0004 6063 3088
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Chapter 1 introduces the Protein Arginine Methyltransferases (PRMTs) as epigenetic regulators that decorate peptidic arginine with methyl groups. Evidence for PRMT involvement in cancer pathogenesis is reviewed and their plausibility as therapeutic targets is introduced. The methylation patterns conferred by the PRMTs is described, and the existence of novel patterns is considered. Techniques for assaying PRMT activity are compared and contrasted and a discussion of current PRMT inhibitors is presented. The chapter concludes by outlining the aims of the thesis. Chapter 2 describes synthesis towards novel methylated arginine molecules that are fully protected for inclusion in peptides via solid phase peptide synthesis. Chapter 3 outlines the total synthesis of protected d-monomethylated arginine for peptide synthesis. This methylation pattern is known in yeast but has not yet been identified in humans. Chapter 4 details a new mass spectrometry-based assay that can be applied for inhibitor and substrate analyses. Synthesis of a novel histone peptide containing the d-monomethylated arginine, produced in Chapter 3, is also described and this is tested for relevance as a human epigenetic marker. Novel polymethylation patterns are also explored in a total of five histone peptides. This chapter concludes with discussion of possible methylation pattern rearrangements. Chapter 5 describes the synthesis and testing of two series of putative PRMT inhibitors based on previously identified scaffolds within this research group. Data obtained from three different assays, including that outlined in Chapter 4, are analysed and suggestions as to the direction of PRMT assay design are offered. Chapter 6 provides the experimental data to support Chapters 2-5, including all organic synthesis procedures, protein & peptide syntheses and assay methodology.
Supervisor: Russell, Angela ; Schofield, Chris ; Brennan, Paul Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available