title: Structure-based design and synthesis of triazole-based macrocyclic inhibitors of norovirus protease: Structural, biochemical, spectroscopic, and antiviral studies.
abstract: Outbreaks of acute gastroenteritis caused by noroviruses constitute a public health concern worldwide. To date, there are no approved drugs or vaccines for the management and prophylaxis of norovirus infections. A potentially effective strategy for the development of norovirus therapeutics entails the discovery of inhibitors of norovirus 3CL protease, an enzyme essential for noroviral replication. We describe herein the structure-based design of the first class of permeable, triazole-based macrocyclic inhibitors of norovirus 3C-like protease, as well as pertinent X-ray crystallographic, biochemical, spectroscopic, and antiviral studies.
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, KS 67260, USA.
authors.forename: Pathum M
authors.initials: PM
authors.lastname: Weerawarna
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: Department of Chemistry, Wichita State University, Wichita, KS 67260, USA.
authors.forename: Vishnu C
authors.initials: VC
authors.lastname: Damalanka
authors.affiliation: LiS Consulting, Lawrence, KS 66046, USA.
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Lushington
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, KS 67260, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Alliston
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: D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D029322:Norovirus / Q000187:drug effects*; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism*; D010539:Permeability; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D014230:Triazoles / Q000737:chemistry*
chemical_list: D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D014230:Triazoles; D010447:Peptide Hydrolases
keywords: 3CL protease; Macrocyclic inhibitors; Norovirus; β-strand conformation