title: Design, synthesis, and evaluation of a novel series of macrocyclic inhibitors of norovirus 3CL protease.
abstract: Norovirus infections have a major impact on public health worldwide, yet there is a current dearth of norovirus-specific therapeutics and prophylactics. This report describes the discovery of a novel class of macrocyclic inhibitors of norovirus 3C-like protease, a cysteine protease that is essential for virus replication. SAR, structural, and biochemical studies were carried out to ascertain the effect of structure on pharmacological activity and permeability. Insights gained from these studies have laid a solid foundation for capitalizing on the therapeutic potential of the series of inhibitors described herein.
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, KS 67260, USA.
authors.forename: Vishnu C
authors.initials: VC
authors.lastname: Damalanka
authors.affiliation: Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Yunjeong
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, KS 67260, USA.
authors.forename: Anushka C
authors.initials: AC
authors.lastname: Galasiti Kankanamalage
authors.affiliation: LiS Consulting, Lawrence, KS 66046, USA.
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Lushington
authors.affiliation: Protein Structure Laboratory, The University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Nurjahan
authors.initials: N
authors.lastname: Mehzabeen
authors.affiliation: IMCA-CAT, Hauptman-Woodward Medical Research Institute, APS Argonne National Laboratory, Argonne, IL 60439, USA.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Battaile
authors.affiliation: Protein Structure Laboratory, The University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Lovell
authors.affiliation: Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA. Electronic address: kchang@vet.ksu.edu.
authors.forename: Kyeong-Ok
authors.initials: KO
authors.lastname: Chang
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, KS 67260, USA. Electronic address: bill.groutas@wichita.edu.
authors.forename: William C
authors.initials: WC
authors.lastname: Groutas
mesh_terms: D000086042:3C Viral Proteases; D000818:Animals; D060326:Chemistry Techniques, Synthetic; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D062105:Molecular Docking Simulation; D029322:Norovirus / Q000187:drug effects / Q000201:enzymology*; D010539:Permeability; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D000067996:RAW 264.7 Cells; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases
keywords: 3CLprotease; Macrocyclic inhibitors; Norovirus