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Access Type

WSU Access

Date of Award

January 2020

Degree Type


Degree Name



Biochemistry and Molecular Biology

First Advisor

Ladislau Kovari


Human norovirus is the leading cause of acute gastroenteritis worldwide, affecting every year over 600 million people. Children under the age of five are more at risk with elderly and immune-compromised individuals. Death associated with the disease is reported at approximately 200,000 every year and children account for the vast majority. Human norovirus also entails severe economic losses, with an estimated cost of 60 billion dollars per year. Despite the societal and economic burden associated to this disease, currently there are no vaccines or antiviral therapeutics to prevent or treat this infection. The Norovirus protease (NoV 3CLpro) represents a promising target for the discovery of antiviral agents for the pivotal role it plays in the replicative life of the virus. Starting with two designed peptidomimetic compounds respectively RS-3150 and RS-2905 identified as potent inhibitors against the NoV 3CLpro. A series of thermal shift assays were conducted to study the stability effect of these small molecules on the NoV 3CLpro and validate them for further structural studies. A FRET-based enzyme assay screen was carried out and a ligand-based pharmacophore model was developed with the aim to identify novel, improved, and effective small molecules against the norovirus protease. With 3 to 6° shift difference compound RS-3150 confers a better stability to the NoV 3CLpro than RS-2905, and has been validated by thermal shift assay and compound titration studies as an excellent candidate for future co-crystallography studies with the NoV 3CLpro. The in silico pharmacophore based approach identified a new small molecule inhibitor with similar binding affinity as RS-3150 and better predicted pharmacological properties. Further optimization of this molecule along with the other top hits could represent the groundwork of a new class of inhibitors of the Norovirus protease.

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