Date of Completion

Spring 3-25-2022

Thesis Advisor(s)

James Cole

Honors Major

Biological Sciences

Disciplines

Biochemistry | Molecular Biology

Abstract

The global pandemic caused by the virus SARS-CoV-2 has devastated the world. A flurry of research into the structures and activities of the virus have identified several viable targets for drug therapy, including the endoribonuclease nsp15, also known as EndoU. EndoU has been shown to play a role in diminishing the host cell’s immune response to the virus by cleaving signaling dsRNA, specifically targeting uridine sequences. The development of the crystal structure nsp15 allowed our lab along with others to perform virtual screenings to identify inhibitors that might be able to dock at the active site and inhibit the activity of the enzyme. Potential inhibitors were screened through a FRET-based enzyme assay and hits were then titrated to examine potency of the inhibitor. Although no new hits for inhibitors were identified, I was able to characterize some known inhibitors and the effect that a divalent ion has on the inhibition of the enzyme. For all of our identified inhibitors, there is increased effectiveness when the reaction is done in the presence of Mn2+ rather than Mg2+. Further research into the binding of the divalent ion and the active site of the enzyme is needed to further characterize the role of the divalent ion cofactor and to find better inhibitors that could be used as drug therapy treatments of COVID-19.

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