title: Structure-based exploration and exploitation of the S4subsite of norovirus 3CL protease in the design of potent and permeable inhibitors.
abstract: Human noroviruses are the primary cause of epidemic and sporadic acute gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised patients and children, constitute a serious public health concern. There are currently no approved human vaccines or norovirus-specific small-molecule therapeutics or prophylactics. Norovirus 3CL protease has recently emerged as a potential therapeutic target for the development of anti-norovirus agents. We hypothesized that the S4subsite of the enzyme may provide an effective means of designing potent and cell permeable inhibitors of the enzyme. We report herein the structure-guided exploration and exploitation of the S4subsite of norovirus 3CL protease in the design and synthesis of effective inhibitors of the protease.
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 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: Athri D
authors.initials: AD
authors.lastname: Rathnayake
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 Chemistry, Wichita State University, Wichita, KS 67260, USA.
authors.forename: Pathum M
authors.initials: PM
authors.lastname: Weerawarna
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, KS 67260, USA.
authors.forename: Sean T
authors.initials: ST
authors.lastname: Doyle
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, KS 67260, USA.
authors.forename: Amer F
authors.initials: AF
authors.lastname: Alsoudi
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, KS 67260, USA.
authors.forename: D M Padmasankha
authors.initials: DMP
authors.lastname: Dissanayake
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: D002460:Cell Line; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D029322:Norovirus / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D010447:Peptide Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D010539:Permeability; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D011480:Protease Inhibitors; D010447:Peptide Hydrolases
keywords: 3CL protease; Norovirus; Optimization; S4 subsite