Abstract

In Alzheimer's disease (AD), a brain protein called "tau" abnormally clumps and forms neurofibrillary tangles (NFTs), causing damage to brain cells. Ac-PHF6-NH2 is a hexapeptide segment of tau protein that plays a dominant role in tau aggregation and is used as a model to design tau protein aggregation inhibitors. In this research we synthesized four dehydroamino acid (□AA) containing PHF6 analogues with △Abu (derived from L-threonine) and △Val (derived from □-OH-Valine) at position 2 or 3 via dehydrations or azlactone ring-openings as key reactions. We evaluated their proteolytic resistance, ability to inhibit aggregation of PHF6, and impact on the morphology of preformed PHF6 fibrils. As a result, we obtained peptides 2-1–2-4 as a new class of proteolytically stable hexapeptide □-sheet breakers. Z-ΔAbu-containing peptide 2-1 and ΔVal-containing peptide 2-4 were highly resistant to proteolysis. ΔAA-containing peptides at position 2 (2-1 and 2-2) showed potent activity as inhibitors of aggregation as demonstrated by circular dichroism, transmission electron microscopy and Thioflavin T assays. The data support the potential of Z-ΔAbu-containing peptide 2-1 to function as a scaffold for discovering new treatments for Alzheimer disease. The total synthesis of Tunicyclin C 4-1 was achieved by applying a novel serine ligation method based on a Mitsunobu reaction followed by O-to-N acyl transfer. The peptide sequence of tunicyclin C made it a challenging target because of the presence of a proline adjacent to a serine. While that is a limitation in other ligation methods, we successfully used the Pro-Ser junction as a ligation site to construct tunicyclin C 4-1, thereby demonstrating the advantages of this novel ligation method.

Degree

PhD

College and Department

Computational, Mathematical, and Physical Sciences; Chemistry and Biochemistry

Rights

https://lib.byu.edu/about/copyright/

Date Submitted

2026-08-12

Document Type

Dissertation

Keywords

peptides, dehydroamino acids, proteolysis, PHF6 aggregation inhibitors, dehydration, azlactone ring-openings, tunicyclin C, serine ligation, Mitsunobu reaction, O-to-N acyl transfer

Language

english

Download

Share

COinS