title: Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies.
abstract: Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.
authors.affiliation: †Department of Chemistry, Wichita State University, 1845 North Fairmount Avenue, Wichita, Kansas 67260, United States.
authors.forename: Anushka C
authors.initials: AC
authors.lastname: Galasiti Kankanamalage
authors.forename: Yunjeong
authors.initials: Y
authors.lastname: Kim
authors.affiliation: †Department of Chemistry, Wichita State University, 1845 North Fairmount Avenue, Wichita, Kansas 67260, United States.
authors.forename: Pathum M
authors.initials: PM
authors.lastname: Weerawarna
authors.affiliation: †Department of Chemistry, Wichita State University, 1845 North Fairmount Avenue, Wichita, Kansas 67260, United States.
authors.forename: Roxanne Adeline Z
authors.initials: RA
authors.lastname: Uy
authors.affiliation: †Department of Chemistry, Wichita State University, 1845 North Fairmount Avenue, Wichita, Kansas 67260, United States.
authors.forename: Vishnu C
authors.initials: VC
authors.lastname: Damalanka
authors.affiliation: †Department of Chemistry, Wichita State University, 1845 North Fairmount Avenue, Wichita, Kansas 67260, United States.
authors.forename: Sivakoteswara Rao
authors.initials: SR
authors.lastname: Mandadapu
authors.affiliation: †Department of Chemistry, Wichita State University, 1845 North Fairmount Avenue, Wichita, Kansas 67260, United States.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Alliston
authors.affiliation: §Protein Structure Laboratory,The University of Kansas, Lawrence, Kansas 66047, United States.
authors.forename: Nurjahan
authors.initials: N
authors.lastname: Mehzabeen
authors.affiliation: ∥IMCA-CAT, Hauptman-Woodward Medical Research Institute, APS Argonne National Laboratory, Argonne, Illinois 60439, United States.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Battaile
authors.affiliation: §Protein Structure Laboratory,The University of Kansas, Lawrence, Kansas 66047, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Lovell
authors.forename: Kyeong-Ok
authors.initials: KO
authors.lastname: Chang
authors.affiliation: †Department of Chemistry, Wichita State University, 1845 North Fairmount Avenue, Wichita, Kansas 67260, United States.
authors.forename: William C
authors.initials: WC
authors.lastname: Groutas
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D000086782:Coronavirus 3C Proteases; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D029322:Norovirus / Q000187:drug effects / Q000201:enzymology* / Q000472:pathogenicity; D010447:Peptide Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011480:Protease Inhibitors; D014764:Viral Proteins; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases