Structural and Antiviral Studies of the Human Norovirus GII.4 Protease

Kendall M. Muzzarelli, Benjamin Kuiper, Nicholas Spellmon, Joseph Brunzelle, Justin Hackett, Franck Amblard, Shaoman Zhou, Peng Liu, Iulia A. Kovari, Zhe Yang, Raymond F. Schinazi, Ladislau C. Kovari*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Norovirus is the leading cause of acute gastroenteritis worldwide with a yearly reported 700 million cases driving a 60 billion global socioeconomic burden. With no United States Food and Drug Administration approved therapeutics and the chance for severe chronic infection and life-threatening complications, researchers have identified the protease as a potential target. However, drug development has focused on the norovirus GI.1 strain despite its accounting for less than 5% of all outbreaks. Our lab aims to change focus for norovirus drug design from GI.1 to the highly infective GII.4, responsible for more than 50% of all outbreaks worldwide. With the first published crystal structure of the norovirus GII.4 protease, we have identified several significant differences in the structure and active site that have hindered development of a potent inhibitor targeting the norovirus GII.4 protease. With these new insights, we have begun designing compounds that demonstrate increased inhibition of the clinically most relevant norovirus GII.4 strain.

Original languageEnglish (US)
JournalBiochemistry
DOIs
StateAccepted/In press - Jan 1 2019

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Norovirus
Antiviral Agents
Peptide Hydrolases
Pharmaceutical Preparations
Disease Outbreaks
Crystal structure
Drug Design
Gastroenteritis
United States Food and Drug Administration
Catalytic Domain
Research Personnel
Infection

ASJC Scopus subject areas

  • Biochemistry

Cite this

Muzzarelli, K. M., Kuiper, B., Spellmon, N., Brunzelle, J., Hackett, J., Amblard, F., ... Kovari, L. C. (Accepted/In press). Structural and Antiviral Studies of the Human Norovirus GII.4 Protease. Biochemistry. https://doi.org/10.1021/acs.biochem.8b01063
Muzzarelli, Kendall M. ; Kuiper, Benjamin ; Spellmon, Nicholas ; Brunzelle, Joseph ; Hackett, Justin ; Amblard, Franck ; Zhou, Shaoman ; Liu, Peng ; Kovari, Iulia A. ; Yang, Zhe ; Schinazi, Raymond F. ; Kovari, Ladislau C. / Structural and Antiviral Studies of the Human Norovirus GII.4 Protease. In: Biochemistry. 2019.
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Muzzarelli, KM, Kuiper, B, Spellmon, N, Brunzelle, J, Hackett, J, Amblard, F, Zhou, S, Liu, P, Kovari, IA, Yang, Z, Schinazi, RF & Kovari, LC 2019, 'Structural and Antiviral Studies of the Human Norovirus GII.4 Protease', Biochemistry. https://doi.org/10.1021/acs.biochem.8b01063

Structural and Antiviral Studies of the Human Norovirus GII.4 Protease. / Muzzarelli, Kendall M.; Kuiper, Benjamin; Spellmon, Nicholas; Brunzelle, Joseph; Hackett, Justin; Amblard, Franck; Zhou, Shaoman; Liu, Peng; Kovari, Iulia A.; Yang, Zhe; Schinazi, Raymond F.; Kovari, Ladislau C.

In: Biochemistry, 01.01.2019.

Research output: Contribution to journalArticle

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AU - Hackett, Justin

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AU - Zhou, Shaoman

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