FAUST – Foldamers as Unnatural Signal Transducers

Abstract

The cell membrane is a fundamental barrier in biology, compartmentalising different components in a cell. Its primary role is to control the movement of hydrophilic molecules in and out of the cell, with several proteins operating within its structure that regulate this process. Malfunction in these proteins can lead to diseases such as cystic fibrosis. The development of artificial systems that replicate the function of membrane proteins has gathered significant attention in recent years. If the function of a membrane protein can be achieved using a much simpler artificial analogue, this allows a greater insight into its mode of action including signal transduction, membrane translocation etc. Alternatively, artificial systems can be designed to operate via a novel mode of action. These biomimetic systems can potentially be used as therapeutics in the future. Peptides containing Aib monomers within their structure can form ion channels in the membrane of bacteria. If a peptide is constructed with a high percentage of this monomer, they will exist in a 310 helix, with equal population of M and P screw-sense. Switching between these two screw-senses allows for signal transduction from the N- to C-terminus. By appending a binding pocket at the C-terminus of an Aib foldamer, allosteric control, induced by the opposing terminus, over the conformation of this pocket was explored. Chloride-binding squaramide units were attached to this newly developed site and their selective ionophoric activity in a phospholipid bilayer were investigated. Steroids are also a common component of cell membranes. Their rigidity and lipophilicity contribute to the fluidity of the bilayer. Ethinyl estradiol (EE) is a steroidal derivative, where previous work show that EE-based dimers exist in two conformations: anti and syn. Only the anti-conformer of this dimer can span the length of a bilayer. Synthesis of this dimer, derivatised with functional groups, is described. Phenylthiosemicarbazone (PTSC), a pH sensitive chloride-binding unit, is appended to the molecule. Using other control compounds in vesicles, it’s shown that switching between the anti- and syn-conformation is key for the transport of chloride across a phospholipid bilayer.

Date of Award	1 Aug 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	John Burthem (Supervisor) & Simon Webb (Supervisor)