Peptide foldamers for artificial signal transduction

UoM administered thesis: Phd

  • Authors:
  • Natasha Eccles

Abstract

Signal transduction is one of the most fundamental biochemical processes that occurs in living organisms and involves the transmission of molecular signals from a cell's exterior to its interior. Foldamers of 2-aminoisobutyric acid (Aib) have shown potential in the creation of a transducer of structural information across nm distances, through a variety of covalent and non-covalent interactions both in solution and aqueous environment. This thesis details the advancement of these helical systems towards a functioning synthetic GPCR mimic capable of signal transduction. Foldamers containing ZnII-recognition sites at the N-terminus were used to recognise chiral carboxylates that switch on signal transduction and conformation control. A C-terminal glycinamide spectroscopic reporter was used to detect this conformation control in solution. A [ZnII(BQPA)]-binding site was pivotal for the creation of a foldamer as a dual NMR and CD probe which cannot only sense helical screw-sense preferences but also sense enantioselectivity of the binding carboxylate. An attempt to activate this functioning foldamer by the binding of a messenger, produced from a desymmetrisation reaction, was also described. An alternative C-terminal reporter was also assessed, not only in solution but in artificial membranes. A highly sensitive bis(pyrene) reporter was exploited for the fluorometric detection of induced screw-sense preferences in covalently controlled Aib foldamers. The effect of phospholipid chirality on foldamer conformation was also explored through the synthesis and incorporation of enantiomeric foldamers bearing the bis(pyrene) reporter. Finally, the synthesis of a ruthenium transfer hydrogenation catalyst and its attachment to Aib foldamers was explored aiming to create a foldamer that can initiate remote catalysis once activated.

Details

Original languageEnglish
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Supervisors/Advisors
Award date1 Aug 2019