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.