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Title: Synthetic strategies towards challenging PPI drug targets
Author: Moore, Thomas Oliver
ISNI:       0000 0004 5992 2747
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2016
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Protein-protein interactions (PPIs) present a challenging target for the development of inhibitors, due to the large size and lipophilicity of protein binding sites. Because of this, work that is able to increase our understanding of how PPI inhibitors can be better developed is of great value. In unusual cases, approved drug compounds are able to exhibit excellent pharmacological (PK) profiles despite having unfavourable physical properties. New methodology was developed whereby the solubilising side chains found in one such compound, daclatasvir, could be incorporated onto aryl-bromides using palladium-catalysed C-H activation. The scope of the reaction was tested, and in 18 different examples the C-H activation was found to be successful 11 times.1 This methodology has application in the potential synthesis of cell-permeable PPI inhibitors. Inhibiting the PALB2/BRCA2 PPI has the potential to produce synthetic lethality in cancerous cells with damaged DNA repair mechanisms. Computational techniques were used to design small-molecule and miniprotein mimetics of BRCA2, which could potentially competitively inhibit PALB2/BRCA2. This resulted in the purchase of 10 miniprotein sequences ready for testing, one of which has been proven to have significant helical secondary structure. The synthesis of small molecule α-helical mimetics of BRCA2 has also been carried out, with one compound ready for biological testing and the synthesis of two others close to completion. Publications: 1 T. O. Moore, M. Paradowski and S. E. Ward, Org. Biomol. Chem., 2016, 14, 3307–3313.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD0415 Biochemistry