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Abstract
The recent introduction of a novel coronavirus to humans has established a measure of foresight regarding the utility of progressive research and at-hand therapeutics to use in the face of viral disease. Following the introduction of the pathogenic SARS-2 coronavirus to humans, multiple variant strains have evolved and continue to adapt and cause disease. Despite current prevalence of somewhat attenuated lineages, persistent symptoms reveal the capacity for SARS-CoV-2 to manifest disease long after acute infection has resolved. These events have recently established a strong connection between viral infection and lingering fatigue symptoms, highlighting the need for therapeutic measures to restore cellular balances in acute and post-acute stages of disease. In this work, I investigate the potential applications of drugs derived from naturally occurring substances and chemically modified against SARS-CoV-2. Tetrahydro-beta-carboline compounds have a broad array of biologically active properties that are of interest in the context of COVID-19 and the various post-acute sequelae of disease. I first investigated the bioactive functions of modified drugs during infection in Vero E6 cells. Using multiple methods to identify drug activity in-vitro, I established differential effects of the drugs contributed by modifications to the chemical core. Results from the full panel of drugs revealed chemical features that confer desirable activity and drugs with cytoprotective antiviral effects were further characterized. I then used lung epithelial cells to establish the specificity of the drugs in a model of the primary site of infection. Assay of two cell lines revealed tissue-specific antiviral activity, but conserved cytoprotective effects with specific chemical modifications. I then identified putative mechanistic drug targets by chemical similarity and validate hits by analysis of gene expression in the two in-vitro cell models. The results obtained in my work reveal these modified compounds to have bioactive and therapeutic properties during infection, dependent on the modification to the core. The modified panel used here establishes different applications for tetrahydro-beta-carbolines during infection and provides insight into the specific effects and modifications which can be optimized as a therapeutic platform for viral disease.