Date of Award

Winter 3-21-2026

Document Type

Dissertation

Degree Name

Ph.D. in Chemistry and Biochemistry

Organizational Unit

College of Natural Science and Mathematics, Chemistry and Biochemistry

First Advisor

Sunil Kumar

Second Advisor

Brady T. Worrell

Third Advisor

Brian W. Michel

Fourth Advisor

Scott Horowitz

Fifth Advisor

Daniel A. Linesman

Copyright Statement / License for Reuse

All Rights Reserved
All Rights Reserved.

Keywords

Alzheimer's Disease, Foldamers, Neurodegeneration, Oligoamides, Parkinson's Disease, Protein mimetics

Abstract

Protein-Protein interactions are imperative for the regulation of a myriad of physiological processes including cellular homeostasis, cell signaling, immune response, genetic replication, and metabolism. Upon mutation or under conditions of cellular stress, proteins can become misfolded leading to aberrant Protein-Protein interactions (aPPIs). These aPPIs are highly implicated in the development and progression of numerous diseases including neurodegenerative disease and cancer. Of the most prominent aPPI related diseases are Alzheimer’s disease (AD) and synucleinopathies such as Parkinson’s disease (PD). In the progression of aPPIs, misfolded proteins interact in an intermolecular fashion which can lead to loss of function of the protein and the accumulation of toxic protein aggregates and neuronal cell death. There are currently no therapeutic options for those afflicted with neurodegeneration and prevalence of the diseases continues to increase at an alarming rate.

The modulation of disease-related aPPIs is a classically challenging task, as the interactions occur between a wide diversity of chemical modalities and across large protein surface areas, hence traditional small-molecule therapeutics are typically rendered ineffective. One class of ligands with a demonstrated ability to abrogate aPPIs are known as peptide mimetic scaffolds. These scaffolds include that of the Oligoquinoline (OQ) and Oligopyridylamide (OP) framework, each with advantageous properties. These ligands consist of an aromatic backbone structure that is chemically diversified on its surface, capable of mimicking the intermolecular interactions of proteins. OQs are dubbed foldamer mimetics as they adopt a helical conformation and orient their sidechains with spacing similar to that of the secondary structures of proteins. Similarly, OP scaffolds also mimic α-helical structures by adopting a linear conformation that places the sidechain functionalities in alignment with the amino acid residues present on the face of an α-helix.

In the present work, we have identified OQ and OP ligands capable of modulating disease-related aPPIs as targeted therapeutics for neurodegeneration. We identified an OQ foldamer-based ligand (SK-129) that potently inhibits the aggregation of αS in numerous PD models. The ligand was capable of inhibiting αS aggregation as well as the co-aggregation of αS and Tau by targeting toxic oligomeric αS species. The ligand further demonstrated favorable pharmaceutical properties and rescued disease phenotypes in in vivo models.

Towards the development of OP ligands as therapeutics, we pioneered a common-precursor synthetic platform to expand chemical diversity and the magnitude of OP libraries. This work was validated in the investigation of an OP analog that potently inhibited Aβ aggregation and rescued AD phenotypes in in vivo models. Using a similar methodology in combination with a 2D fragment-assisted structure-based technique, we further synthesized a library of OP mimetics for the modulation of tauopathies, identifying a potent OP mimetic towards the inhibition of tau aggregation. Expanding from the common-precursor method, we implemented synthetic modifications to the backbone structure of OPs allowing for a rapid and high-throughput synthesis of hybrid oligoamide scaffolds (LD-HOPS) using late-stage diversification and combinatorial techniques.

Copyright Date

3-2026

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Rights Holder

Ryan A. Dohoney

Provenance

Received from ProQuest

File Format

application/pdf

Language

English (eng)

Extent

629 pgs

File Size

81.5 MB

Download

Available for download on Friday, April 14, 2028



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