Design and evaluation of Trypanosoma brucei metacaspase inhibitors.
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.
Berg
Maya
M
Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
Van der Veken
Pieter
P
Joossens
Jurgen
J
Muthusamy
Venkatraj
V
Breugelmans
Matthias
M
Moss
Catherine X
CX
Rudolf
Jana
J
Cos
Paul
P
Coombs
Graham H
GH
Maes
Louis
L
Haemers
Achiel
A
Mottram
Jeremy C
JC
Augustyns
Koen
K
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*
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D014344:Trypanocidal Agents; D020169:Caspases