Target-directed synthesis of protein-protein interaction inhibitors
File(s)
Author(s)
Sharma, Sachi
Type
Thesis
Abstract
Protein-protein interactions (PPIs) are prevalent across biology and play a central role in various cellular pathways. As aberrant interactions often manifest in the form of disease, the modulation of PPIs is of significant interest. A promising strategy for the development of PPI inhibitors exploits α-helical secondary structures, which are prevalent at many PPI interfaces. To date, the α-helix mimetic scaffolds reported fail to explore a diverse chemical space. This lack of diversity, in conjunction with the limited advancement of high-throughput screens in the context of PPIs, calls for the development of a novel approach for the synthesis of PPI inhibitors, whereby a large chemical space can be rapidly explored.
Herein the design and optimisation of a high-throughput target-directed screen is presented. This was designed in a manner where the natural selectivity of the native helix towards the protein of interest is exploited. For the development of this concept BCL-XL/BAK was chosen as the model PPI. A two-pronged approach was taken, whereby in parallel both a peptidic and a hybrid mimetic route was developed. A series of BAK derived peptidic mimetics was synthesised featuring a nucleophilic thiol. This library was screened with a diverse electrophilic fragment library to generate functionalised mimetics. The binding affinity of these functionalised mimetics towards BCL-XL was subsequently evaluated, with the hits identified serving to inform a future target- directed assay variant to be performed in the presence of the target protein. The hybrid pathway was designed where both peptidic and non-natural residues would be integrated into a single mimetic...
Herein the design and optimisation of a high-throughput target-directed screen is presented. This was designed in a manner where the natural selectivity of the native helix towards the protein of interest is exploited. For the development of this concept BCL-XL/BAK was chosen as the model PPI. A two-pronged approach was taken, whereby in parallel both a peptidic and a hybrid mimetic route was developed. A series of BAK derived peptidic mimetics was synthesised featuring a nucleophilic thiol. This library was screened with a diverse electrophilic fragment library to generate functionalised mimetics. The binding affinity of these functionalised mimetics towards BCL-XL was subsequently evaluated, with the hits identified serving to inform a future target- directed assay variant to be performed in the presence of the target protein. The hybrid pathway was designed where both peptidic and non-natural residues would be integrated into a single mimetic...
Version
Open Access
Date Issued
2024-03-15
Date Awarded
2024-06-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Barnard, Anna
Armstrong, Alan
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)