Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.692506
Title: Chemical biology tools to explore the activities and mechanisms of Class I HDAC corepressor complexes
Author: Robertson, Naomi Stephanie
ISNI:       0000 0004 5918 9979
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2016
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Abstract:
Isoform selective histone deacetylase (HDAC) inhibitors are urgently required to investigate HDAC isoform phenotypes and provide targeted therapeutics. Class 1 HDACs (1, 2 and 3) are recruited into large multi-subunit co-repressor complexes for maximal activity. However, little attention has been paid to targeting the disruption of these protein-protein interactions (PPIs) and so represents a novel approach to develop more specific therapeutics and chemical probes. This thesis describes the design, synthesis and evaluation of stapled peptide analogues of the SMRT-DAD protein. A systematic, structure based approach was taken to design the second generation stapled peptides containing phosphotyrosine residues. These were shown to be super activators of the HDAC3:SMRT-DAD corepressor complex. The synthesis of a hydroxamic acid amino acid is also described and an improvement on the current synthetic scheme is discussed. A novel hydroxamic acid containing histone H4 tail peptide was then prepared which was shown to be an inhibitor of the HDAC1:MTA1 corepressor complex with an IC50 of 366 nM. A crystal structure of this inhibitor peptide bound in the active site of HDAC1 was also obtained. The challenging synthesis of a series of histone H3 (1-21) tail sequence peptides has also been described. NMR experiments were carried out using these peptides to study both the demethylase and deacetylase activities of the ternary LSD1:CoREST:HDAC1. The deacetylase activity of HDAC1 has been shown to be much faster than the demethylase activity of LSD1. In order to obtain a crystal structure of the ternary LSD1:CoREST:HDAC1 complex and to determine the distance between the LSD1 and the HDAC1 components, three dual peptide inhibitors based on SNAIL have been designed and synthesised. These crystallisation experiments and biological studies are in progress.
Supervisor: Jamieson, Andrew ; Schwabe, John Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.692506  DOI: Not available
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