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

• Authors: Kendall M. Muzzarelli, Wayne State University; Benjamin Kuiper, Wayne State University; Nicholas Spellmon, Wayne State University; Joseph Brunzelle, Northwestern University; Justin Hackett, Wayne State University; Franck Amblard, Emory University; Shaoman Zhou, Emory University; Peng Liu, Emory University; Julia A. Kovari, Wayne State University; Zhe Yang, Wayne State University; Raymond Schinazi, Emory University; Ladislau C. Kovari, Wayne State University
• Journal Title: BIOCHEMISTRY
• Volume: Volume 58, Number 7
• Publisher: AMER CHEMICAL SOC | 2019-02-19, Pages 900-907
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1021/acs.biochem.8b01063
• Subjects: Biology, Molecular; Chemistry, Biochemistry
• Keywords: Science & Technology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; CRYSTALLOGRAPHIC STRUCTURE; STRUCTURE REFINEMENT; INHIBITION; 3C

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.