Date of Award
Summer 2023
Document Type
Open Access Dissertation
Department
College of Pharmacy
First Advisor
Michael Shtutman
Abstract
HIV infection remains a significant global health challenge. Despite the widespread use of combination antiretroviral therapy, people living with HIV (PLWH) still face a disproportionate burden of major health problems. One of these problems is HIV-associated neurocognitive disorders (HAND), which includes a spectrum of cognitive, motor, and behavioral impairments. Although severe forms of HAND have decreased, milder forms are on the rise, posing a significant obstacle for PLWH.
The persistence of HIV in the central nervous system (CNS) is a challenge of HAND treatment and involves a combination of factors, including neurotoxic HIV proteins, chronic neuroinflammation, and comorbidity with substance abuse disorders (SUDs). SUDs exacerbate cognitive disruption associated with HIV infection and continue to compromise the quality of life of PLWH.
To tackle this problem, we investigated the role of microglia in the neurodegeneration exacerbated by drug use. Microglia are not only the primary host cells of HIV but also a major source of viral reservoirs within the brain, making their role in the pathogenesis of HAND in the human nervous system crucial. We employed an artificial intelligence (AI)-based text mining system to uncover more promising therapeutic compounds that are further along the drug development pipeline. By repurposing already animal tested and abundantly researched inhibitors, Itaconate and RK-33, as potential therapeutics for HAND and SUD, which has not been studied in the context of HAND and SUD, we can provide new possibilities for eventual therapy options for patients suffering from these conditions.
Moreover, these AI-based compound results can be expanded to different biological contexts. Here, we explored the broader implications of compound RK-33 in the context of stress response, particularly SG dynamics. Pharmacological inhibition of SG components was not attempted before, and this successful data showing pharmacological manipulation of cell stress response can have broader implications in basic biological phenomena.
Rights
© 2023, Biyun Celia Cui
Recommended Citation
Cui, B. C.(2023). Drug Repurposing: New Mechanisms and Applications of Existing Compounds. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/7371