Graduation Year

2019

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

James W. Leahy, Ph.D.

Committee Member

Bill J. Baker, Ph.D.

Committee Member

Jianfeng Cai, Ph.D.

Committee Member

Laura Blair, Ph.D.

Keywords

Alzheimer's, FKBP51, leishmaniasis, neurodegenerative, pentamidine, benztropine, PTSD

Abstract

Neurological disorders have multiple etiologies such as genetics and age. Stress related disorders are becoming more common and diagnosed more often. Mental health disorders are no longer being treated as purely psychological. Mechanisms into the underlying factors of these disorders continue to bring this area to new frontiers. Chapter 2 of this dissertation focuses on the efforts made to prove the association of the protein FKBP51 to the stress response. We synthesized and used a molecular tool to discover and prove these interactions.

The study of neurodegenerative diseases is of continued importance as the world reaches record numbers of an aging population. Neurodegenerative diseases predominate in Western countries and it is hypothesized that cultural and socioeconomic factors are involved. Treatments for neurodegenerative diseases are ineffective and there is a need for new drug discovery research into these areas. Chapter 3 of this dissertation focuses on efforts in making new analogs of a known Hsp70 inhibitor, JG-98. This compound is known to clear tau from neurons but is not particularly blood-brain-barrier permeable. Our research efforts focused on optimizing these two factors toward more effective compounds against tauopathies.

Infectious diseases are a major cause of human death and suffering worldwide. This is especially the case in developing countries with limited access to health care and proper sanitation. Current treatments for infectious diseases are often toxic or expensive. Chapter 4 of this dissertation is related to infectious diseases and our efforts in making an analog of a known drug, pentamidine. Pentamidine is used as a treatment for multiple infectious diseases but carries toxic side effects. Our research focuses on making changes to pentamidine to improve its properties with bioavailability. We further hope this new compound has an improved toxicity profile over pentamidine.

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