title: Design and evaluation of Trypanosoma brucei metacaspase inhibitors.
abstract: Metacaspase (MCA) is an important enzyme in Trypanosoma brucei, absent from humans and differing significantly from the orthologous human caspases. Therefore MCA constitutes a new attractive drug target for antiparasitic chemotherapeutics, which needs further characterization to support the discovery of innovative drug candidates. A first series of inhibitors has been prepared on the basis of known substrate specificity and the predicted catalytic mechanism of the enzyme. In this Letter we present the first inhibitors of TbMCA2 with low micromolar enzymatic and antiparasitic activity in vitro combined with low cytotoxicity.
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Maya
authors.initials: M
authors.lastname: Berg
authors.forename: Pieter
authors.initials: P
authors.lastname: Van der Veken
authors.forename: Jurgen
authors.initials: J
authors.lastname: Joossens
authors.forename: Venkatraj
authors.initials: V
authors.lastname: Muthusamy
authors.forename: Matthias
authors.initials: M
authors.lastname: Breugelmans
authors.forename: Catherine X
authors.initials: CX
authors.lastname: Moss
authors.forename: Jana
authors.initials: J
authors.lastname: Rudolf
authors.forename: Paul
authors.initials: P
authors.lastname: Cos
authors.forename: Graham H
authors.initials: GH
authors.lastname: Coombs
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Achiel
authors.initials: A
authors.lastname: Haemers
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Mottram
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
mesh_terms: D000818:Animals; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002384:Catalysis; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D013379:Substrate Specificity; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000201:enzymology*
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D014344:Trypanocidal Agents; D020169:Caspases