Diamino Diacid Macrocyclization of Apelin and Neopetrosiamide

  • Author / Creator
    Pascoe, Cameron
  • Peptides can elicit a whole host of beneficial physiological effects. The market for peptide-based therapeutics is rapidly expanding due to their extreme specificity and low toxicity. Conversely, they often possess poor bioavailability, stability, pharmacokinetics and cell permeability, limiting their therapeutic potential. Macrocyclization of peptides has been used to increased peptide stability and cell permeability. Described herein is the expansion of chemistry to increase the accessibility of orthogonally protected diamino diacids and the efforts towards their incorporation to create carbon-based macrocycles of two biologically active peptides. An investigation into their activity through the use of biological assays is also presented.
    Chapter 2 discusses efforts toward the synthesis of differentially protected diamino diacids. These molecules can be used to efficiently incorporate macrocycles into peptides and mimic natural linkages that are susceptible to degradation and strengthen them. The attempted use of a solid support to assist the synthesis of diaminosuberic acid analogues is described along with the use of a 1,2-benzenedimethanol scaffold to expand the orthogonally protected diamino diacids available using this methodology from one to four. Each of the synthesized diamino diacids analogues produced is immediately SPPS amenable.
    Chapter 3 discusses the synthesis of methylene analogues of neopetrosiamide as potential antimetastatic agents. Neopetrosiamide is a 28-residue peptide isolated from a marine sponge that contains three disulfide bonds. It has been shown to inhibit mammalian tumour invasion in vitro but requires precise connectivity of the disulfide bonds for activity. Single disulfide bond replacement by methylene bridges through pre-stapling of the peptide using orthogonally protected diaminosuberic acid results in three new active analogues comparable in activity to the native peptide and enhances correct folding of the remaining disulfide bonds. Formation of the remaining disulfide bonds is simplified to a single step, followed by HPLC purification.
    Chapter 4 discusses the synthesis of apelin analogues. Apelin is a peptide that evokes significant cardio-protective effects such as increased myocardial contractility, increased heart rate and blood pressure lowering. However, apelin’s therapeutic use is drastically hindered due to rapid degradation in plasma due to multiple degradation sites. Attempts for more stable analogues by isostere substitution of the KLKB1 degradation sites resulted in stable analogues able to evoke a biological response, however, at concentrations too high to be effective. Additional analogues incorporating macrocycles of the C-terminus with orthogonally protected diamino diacids to increase plasma stability and cell permeability were synthesized but proved to be inactive.

  • Subjects / Keywords
  • Graduation date
    Fall 2022
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.