Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Barr, Stephen D.

Abstract

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused extensive mortality and societal disruption. BOLD-100 is a novel anticancer therapeutic being considered to treat COVID-19. We hypothesized that BOLD-100 inhibits SARS-CoV-2 replication and progression of COVID-19. Using Western blotting, quantitative RT-PCR, and cell viability assays, we determined that BOLD-100 inhibits SARS-CoV-2 replication in vitro. RNA sequencing analysis demonstrated that BOLD-100 inhibits virus-induced transcriptional changes in infected cells. Intravenous BOLD-100 treatment of SARS-CoV-2-infected hamsters did not significantly alter body weight, lung viral load or pathological lesions. Finally, we showed that the antiviral activity of BOLD-100 is not specific for SARS-CoV-2 and can also inhibit replication of Human Immunodeficiency Virus type 1 and Human Adenovirus type 5. This study identifies BOLD-100 as a novel antiviral agent and will inform its future preclinical development.

Summary for Lay Audience

The COVID-19 pandemic has caused widespread illness and mortality worldwide, and threatens many more lives in the months to come. There is an urgent need to discover and test new treatments to treat patients with COVID-19. BOLD-100 is a promising new drug that was originally developed as an anticancer therapeutic, but has been shown to potently inhibit SARS-CoV-2 (the virus that causes COVID-19) in initial experiments.

In this study, we first characterized the antiviral potential of BOLD-100 against SARS-CoV-2 by measuring its ability to stop the virus from reproducing and killing infected cells. Subsequently, we determined that BOLD-100 inhibits changes in cellular gene expression that occur upon infection with SARS-CoV-2. We then established a Syrian hamster model of SARS-CoV-2 infection to test the therapeutic impact of BOLD-100 on COVID-19 in live animals. We determined the maximum tolerated dose of BOLD-100 in hamsters, in addition to the appropriate dosage of SARS-CoV-2 for infection. BOLD-100 treatment in SARS-CoV-2 infected hamsters did not significantly reduce virus replication or tissue damage in the lungs. However, further refinements to our hamster model are possible to maximize the effect of BOLD-100. Finally, we demonstrated that the antiviral activity of BOLD-100 is not specific for SARS-CoV-2, and that it additionally inhibits the replication of Human Immunodeficiency Virus 1 and Human Adenovirus type 5. In conclusion, we identified BOLD-100 as a novel antiviral therapeutic with antiviral activity against SARS-CoV-2 and additional viruses of public health concern, but with limited activity in a hamster model of COVID-19. This information will support the further development of BOLD-100, and inform future preclinical studies. Identification of new antiviral drugs will provide additional treatment options for vulnerable patients and may alleviate the burden of future pandemics.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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