Graduation Year
2024
Document Type
Dissertation
Degree
Ph.D.
Degree Name
Doctor of Philosophy (Ph.D.)
Degree Granting Department
Chemistry
Major Professor
Jianfeng Cai, Ph.D.
Committee Member
James Leahy, Ph.D.
Committee Member
Wenqi Liu, Ph.D.
Committee Member
Feng Cheng, Ph.D.
Keywords
Alzheimer’s disease, Aβ, ype-2-diabetes, hIAPP, peptidomimetics, β-sheet
Abstract
Many proteins contain fragments that become structured upon binding to specific targets or through self-association. Notable examples of such disorder-to-order transitions include amyloidogenic proteins like amyloid-β peptide (Aβ) and tau peptide in Alzheimer's disease, α-Synuclein in Parkinson's disease, and hIAPP in type 2 diabetes, and so on. These regions can aggregate into amyloid fibrils through β -sheet stacking, contributing to amyloidosis and related diseases. Although direct link between amyloid formation and neurodegenerative disease development is not fully understood, developing effective inhibitors of these amyloid peptides remains promising both for fundamental research and therapeutical advance.
We have developed a new class of sequence-specific peptidomimetics called AApeptides. Our findings demonstrate that AApeptides derivatives can fold into well-defined protein-like structures and show significant potential in recognizing proteins and nucleic acids. Thus, AApeptides hold promise as valuable tools and potential drug candidates for probing and modulating essential cellular processes.
In this dissertation, I develop AApeptide-based scaffolds, including D-sulfonyl-γ-AApeptides helix and β-sheet scaffold, which are both confirmed by the crystal structure, and the application of both scaffolds for the inhibitor design towards several targets, including Aβ42, tau peptide and hIAPP. For the Aβ42, we first make use of the helix scaffold to interact and stabilize the central helix domain within Aβ42, which could effectively prevent fibril formation and potential neurotoxicity. Besides, we also develop sulfonyl-γ-AA templated β-sheet scaffold and succeeded in optimizing a lead compound, which could completely inhibit the Aβ oligomerization and disrupt the pre-formed aggregates. For the tau peptide, whose aggregation is related to AD development, we successfully optimized the sheet scaffold-based inhibitors for the tau peptide aggregation. For the IAPP, whose aggregation would result in the β-cell death in type 2 diabetes. We successfully capture the transient helix domain within hIAPP by interacting with the sulfonyl-γ-AApeptides. Further in vivo experiments would be carried out to decipher the bioactivity of these ligands.
Scholar Commons Citation
Liu, Heng, "Development of peptidomimetics based on γ-AApeptide molecular scaffolds to modulate amyloid peptide aggregation" (2024). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/11137
