Macrocyclic peptides have been identified as key backbones in several biologically active compounds. They have been considered as great inspiration in the development of novel cyclic scaffolds in medicinal chemistry, notably in the introduction of α-helically constricted stapled peptides with the ability to mimic biologically relevant α-helices. DNA-binding transcription factors often bind their DNA promoter through an α-helix, making a parallel with stapled peptides as inhibitors. Despite this relevant feature, DNA-binding stapled peptides are highly unrepresented in the literature, as will be discussed here in a review. We also further expand this area of research with a study of DNA binding stapled peptide ana-logues with the goal of optimizing and investigating the DNA binding and antivirulence of an RpoN-based stapled peptide.
Cyclic depsipeptides are highly biologically active natural product molecules however their synthesis can be challenging with the presence of a macrolactone. Due to this complexity, solid phase peptide synthesis strategies have been utilized to access peptide intermediates that can be synthetically macrocyclized using solution phase or on-resin approaches via macrolactam or macrolactone formation. A representative number of total syntheses in the literature is reviewed. Furthermore, we describe here the chemical total synthesis and chemoenzymatic synthesis of seongsanamide E cyclic depesipeptide via thioesterase medi-ated macrolactonization.
Cyclic depsipeptides also play major roles in their producing organisms, notably siderophores capable of chelating and transporting iron. The biosynthesis of fungal siderophores is poorly explored, such as the iterative mechanism of oligomeric compound fusarinine C. We explore the synthesis of the previously never synthesized fusarinine C monomer to be utilized as a di-domain inhibitor of the adenylating-thiolation domains of the non-ribosomal peptide synthetase (NRPS) SidD.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/45654 |
| Date | 22 November 2023 |
| Creators | Paquette, André |
| Contributors | Boddy, Christopher N. |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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