Abstract
This dissertation addresses the challenges associated with cyclic peptides’ inherent shortcomings, notably their water insolubility and cellular membrane impermeability, and explores strategies for enhancing their bioactivity through the incorporation of unnatural amino acids. The dissertation was structured into four chapters, each dedicated to elucidating the central theme of incorporating unnatural amino acids to modulate bioactivity.
Chapter 1 provides a comprehensive introduction, covering fundamental theories, the evolution of related research, and recent advancements in the field. It begins with an overview of Alzheimer's disease development, its associated pathogenesis, and the influence of hydration shells on macromolecular motion, with particular emphasis on the amyloid β cascade hypothesis. Additionally, the chapter discusses the significance of discovering cyclic cell-penetrating peptides and their underlying mechanism models.
Chapter 2 probes into the project's details, focusing on the incorporation of the unnatural amino acid D-glucosaminic acid with a polyhydroxy structure into cyclic peptide sequences. Molecular modeling and Thioflavin T assays were employed to investigate how these peptides impede amyloid β fibrillation, utilizing the understanding into the hydration shell's influence on protein misfolding.
In Chapter 3, the impact of ether and amine linkages derived from trans-4-hydroxy-L-proline on peptide permeability was examined through molecular modeling, live cell imaging, and flow cytometry. The findings highlight the exceptional penetration ability of cyclic cell-penetrating peptide 15 compared to the classic permeable peptide TAT. Moreover, the potential penetration mechanism of peptide 15 was explored using various endocytosis inhibitors.
Chapter 4 provided a concise conclusion, summarizing the findings of the projects. The research presented demonstrates that the limitations inherent in peptide drugs can be effectively addressed through the introduction of unnatural amino acids, offering new avenues for enhancing peptide drug discovery by reshaping their physicochemical and biophysical properties.
Chapter 1 provides a comprehensive introduction, covering fundamental theories, the evolution of related research, and recent advancements in the field. It begins with an overview of Alzheimer's disease development, its associated pathogenesis, and the influence of hydration shells on macromolecular motion, with particular emphasis on the amyloid β cascade hypothesis. Additionally, the chapter discusses the significance of discovering cyclic cell-penetrating peptides and their underlying mechanism models.
Chapter 2 probes into the project's details, focusing on the incorporation of the unnatural amino acid D-glucosaminic acid with a polyhydroxy structure into cyclic peptide sequences. Molecular modeling and Thioflavin T assays were employed to investigate how these peptides impede amyloid β fibrillation, utilizing the understanding into the hydration shell's influence on protein misfolding.
In Chapter 3, the impact of ether and amine linkages derived from trans-4-hydroxy-L-proline on peptide permeability was examined through molecular modeling, live cell imaging, and flow cytometry. The findings highlight the exceptional penetration ability of cyclic cell-penetrating peptide 15 compared to the classic permeable peptide TAT. Moreover, the potential penetration mechanism of peptide 15 was explored using various endocytosis inhibitors.
Chapter 4 provided a concise conclusion, summarizing the findings of the projects. The research presented demonstrates that the limitations inherent in peptide drugs can be effectively addressed through the introduction of unnatural amino acids, offering new avenues for enhancing peptide drug discovery by reshaping their physicochemical and biophysical properties.
| Originalsprog | Engelsk |
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| Forlag | Department of Chemistry, Faculty of Science, University of Copenhagen |
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| Antal sider | 216 |
| Status | Udgivet - 2024 |