Graduation Date

Fall 8-11-2023

Document Type


Degree Name

Doctor of Philosophy (PhD)


Pharmaceutical Sciences

First Advisor

Paul C. Trippier, PhD

Second Advisor

Jonathan L. Vennerstrom, PhD

Third Advisor

Corey R. Hopkins, PhD

Fourth Advisor

Aaron M. Mohs, PhD

MeSH Headings

Medicinal Chemistry, Neuropharmacology


Stroke is the world's second-leading cause of death and disability. Ischemic stroke (IS), a primary subtype of stroke, has ineffective and limited treatment options, resulting in a significant unmet medical need for novel therapies. Tissue plasminogen activator (tPA) is the sole FDA-approved medication now in use; however, it has a narrow therapeutic window (3 to 4.5 h). Unfortunately, few individuals have this opportunity to be diagnosed with stroke in time to begin therapy with tPA. Additionally, treatment with tPA can have major adverse effects, such as bleeding, which can exacerbate the consequences of a stroke on the brain. To overcome these restrictions, this occurrence necessitates the discovery and development of novel therapies. In recent investigations, endopeptidase neurolysin (Nln) has been identified as one of the brain's self-protective components. It plays a vital role in maintaining and recovering normal brain functions after IS. The ability of Nln to deactivate multiple neurotoxins and create some cerebro-protective neuropeptides is one of its most essential functions in the post-IS brain. It has been discovered that this Nln is upregulated during IS, even on the seventh day, and has a beneficial outcome on post-IS. This occurrence prompts us to examine the Nln as a potential target for the discovery of novel therapeutics capable of overcoming the limitations of existing therapies. A virtual high-throughput screen was performed in a first attempt to identify prospective hits as Nln activators, and the top hits were found to be dipeptides. The peptidomimetic strategy was chosen to circumvent the shortcomings of dipeptides, such as metabolic instability and brain impermeability. To discover potent ‘drug-like’ Nln activators, over hundred molecules have been synthesized and evaluated, twenty-five of which have shown activity at single-digit micromolar concentrations, five of which are significantly stable in mouse plasma and brain, and five of which are brain permeable and selective to neurolysin over similar peptidases. Further lead optimization is ongoing to develop highly potent, brain-permeable, stable, and selective Nln activators for developing therapies to treat IS.


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