Darling, William T. P.; (2024) Structural Analysis of Non-Reducible Cyclic Peptides: Insights into Ring Expansion and Contraction. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Peptide therapeutics are the fastest growing sector of the pharmaceutical industry because of the remarkable potency, selectivity, and safety profile typical of peptides, compared with small molecules. A major drawback of peptide therapeutics however is their impractically short biological half-lives. Cyclic peptides have therefore emerged as a class of therapeutics with increased stability as well as increased cell permeability. Both naturally occurring and synthetic cyclic peptides most commonly incorporate a disulfide bond as their bridging mode between two cysteine residues, however this disulfide bond is susceptible to reduction, isomerisation, and nucleophilic attack. Because of this, a plethora of non-reducible disulfide bond mimics have been developed. As biological activity is directly related to the conformation of the therapeutic peptide, the disulfide bond mimics that maintain the bioactive conformation are more likely to retain biological activity. In this thesis, three cyclic analogues of the endogenous peptide angiotensin (1-7) incorporating a thioether, disulfide and methylene thioacetal bridge were synthesised wherein the macrocyclic ring size marginally decreases, or increases, with respect to the disulfide bridged peptide. The solution ensemble conformations of these three peptides were elucidated using an NMR methodology called NAMFIS. It was observed that the major conformations of each peptide are conserved between the series, indicating that small modulations in the macrocyclic ring size are unlikely to cause significant changes in the conformation, and therefore thioether and methylene thioacetal bridging modalities are likely suitable disulfide bond mimics for therapeutic peptides. This thesis also outlines the progress made towards elucidating the solution ensemble of the endogenous peptide vasopressin by NMR to compare with the literature solution ensemble determined by molecular dynamics simulations.

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