title: Identification of lead compounds targeting the cathepsin B-like enzyme of Eimeria tenella.
abstract: Cysteine peptidases have been implicated in the development and pathogenesis of Eimeria. We have identified a single-copy cathepsin B-like cysteine peptidase gene in the genome database of Eimeria tenella (EtCatB). Molecular modeling of the predicted protein suggested that it differs significantly from host enzymes and could be a good drug target. EtCatB was expressed and secreted as a soluble, active, glycosylated mature enzyme from Pichia pastoris. Biochemical characterization of the recombinant enzyme confirmed that it is cathepsin B-like. Screening of a focused library against the enzyme identified three inhibitors (a nitrile, a thiosemicarbazone, and an oxazolone) that can be used as leads for novel drug discovery against Eimeria. The oxazolone scaffold is a novel cysteine peptidase inhibitor; it may thus find widespread use.
authors.affiliation: Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, 120 University Place, Glasgow, Scotland, United Kingdom.
authors.forename: Marie
authors.initials: M
authors.lastname: Schaeffer
authors.forename: Joerg
authors.initials: J
authors.lastname: Schroeder
authors.forename: Anja R
authors.initials: AR
authors.lastname: Heckeroth
authors.forename: Sandra
authors.initials: S
authors.lastname: Noack
authors.forename: Michael
authors.initials: M
authors.lastname: Gassel
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Mottram
authors.forename: Paul M
authors.initials: PM
authors.lastname: Selzer
authors.forename: Graham H
authors.initials: GH
authors.lastname: Coombs
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002645:Chickens; D003001:Cloning, Molecular; D003049:Coccidiostats / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D016786:Eimeria tenella / Q000187:drug effects* / Q000254:growth & development; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009570:Nitriles / Q000494:pharmacology; D010081:Oxazolone / Q000494:pharmacology; D010843:Pichia; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D054852:Small Molecule Libraries; D013379:Substrate Specificity; D013882:Thiosemicarbazones / Q000494:pharmacology
chemical_list: D003049:Coccidiostats; D015853:Cysteine Proteinase Inhibitors; D009570:Nitriles; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D013882:Thiosemicarbazones; D010081:Oxazolone; D002401:Cathepsin B