Use this URL to cite or link to this record in EThOS:
Title: Towards synthetic mutagenesis of aromatic residues in peptides for disrupting protein-protein interactions
Author: Mo, Bingli
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
Availability of Full Text:
Access from EThOS:
Access from Institution:
The research described in this thesis covers two fields of investigation: 1) Development of Peptidic Inhibitors of the IgE-FcєRI Protein-Protein Interaction in Allergy. When Immunoglobulin E (IgE) binds to its high affinity receptor protein FcєRI on the surface of mast cells or blood basophiles, it can cause an immediate allergic reaction by triggering the release of toxic inflammatory agents. Inhibition of the protein-protein interactions (PPIs) between IgE and FcєRI is known to prevent the release of inflammatory agents; thereby effectively targeting allergic disorders. In this thesis, the development of a retro-αFcєRI C-region mimic peptidic inhibitor (named BM1149-Am; IC50 = 77±11 μM av.) from the study of literature peptidic inhibitors is described. Structure-activity relationship (SAR) studies of BM1149-Am using alanine-scan and truncation techniques identified the key structural epitope along the sequence to be Tyr-Tyr-Ile-Val. One of the alanine-scan analogues, [Y8A] BM1149-Am showed a 10-fold improved IC50 value in ELISA assay compared to that of BM1149-Am. 2) Towards Aryl Germane-Based Synthetic Mutagenesis of Peptides Synthetic mutagenesis of aromatic amino acids (AAAs), in particular phenylalanine (Phe) and tyrosine (Tyr), to give biaryl derivatives are of great interest. Such biaryl units are important structural elements in protein-protein interactions (PPI). Biaryls are generally prepared by cross-coupling between aryl metals and aryl halides. In this thesis, fluorous-tagged silyl germanes were studied as the precursor towards a new generation of aryl metals. Silyl germanes were successfully synthesised from commercially available germanium(IV) chloride in eight steps. Literature conditions reported for coupling of both metal hydride and bimetallo group 14 compounds with aryl halides as well as modified variants were screened. Conditions where a CuI-6- methyl-2-(hydroxymethyl)pyridine complex was used as an additive to a Pd(OAc)2- dppf catalyst system was found to be the best, although even these conditions had limited substrate scope.
Supervisor: Leatherbarrow, Robin ; Spivey, Alan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral