Smith, Frances
(2020)
Macrocyclic peptides as inhibitors of protein-protein interactions.
PhD thesis, University of Nottingham.
Abstract
Inhibition of the Keap1-Nrf2 protein-protein interaction (PPI) is thought to have therapeutic potential in several diseases including neurodegenerative conditions such as Alzheimer’s and Parkinson’s, as well as cardiovascular diseases and cancer. Cyclic peptides provide interesting scaffolds that not only display enhanced metabolic stability, but also induce conformational rigidity that may maximise interaction with the target. This project aims to develop peptidomimetic inhibitors of the Keap1-Nrf2 PPI using a portion of the natural binding sequence of a ligand of Keap1 and cyclising with a non-peptide linker.
Chapter 2 discusses the solution phase synthesis of the linear tripeptide Pro-Glu-Thr and coupling to three alkyl chain linkers of differing lengths. The orthogonal protecting group strategy used Boc and Bn groups on the N-terminus and side chains respectively. The C terminal protecting group first used was the phenacyl group, however, due to difficulties in its removal, this was changed to the trimethylsilyl group. Following preparation of the linear peptide, its cyclisation was performed using a variety of conditions, though challenges with racemisation were encountered.
Chapter 3 details the solid phase synthesis of the linear peptides Pro-Glu-Thr-alkyl chain. This was first attempted with a linker between the resin and the peptide which was then activated to the labile linker benzotriazole, resulting in cyclisation under basic conditions. However, as this method failed to yield any cyclic peptide, the peptide was synthesised on resin and cyclised in solution. Once again this resulted in the formation of multiple products. Addition of glycine to the C-terminal of the peptide gave Pro Glu-Thr-Gly-linker. This peptide was successfully cyclised, along with two analogues, and brief molecular modelling and NMR spectroscopy studies were performed on these compounds.
Chapter 4 discusses the cyclisation of the linear peptide by formation of a variety of heterocycles. These procedures were all based upon literature precedent and included the preparation of 1,2,3-triazoles via click chemistry, oxidative diyne coupling, formation of a 1,3,4-oxadiazole, and 1,3-dipolar cycloaddition to give pyrazoles.
Chapter 5 details a catalyst-free 1,3-dipolar cycloaddition of alkynes and stabilised diazo compounds to give pyrazoles. The oxidising reagent TsNIK was used to prepare a variety of α diazophosphonates and were used to generate pyrazoles in both intra- and intermolecular cycloadditions, as well as strain-promoted cycloadditions.
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