title: Improved trypanocidal activities of cathepsin L inhibitors.
abstract: The major lysosomal cysteine proteinase of African trypanosomes is a candidate target for novel chemotherapy of sleeping sickness. This cathepsin L-like enzyme is termed rhodesain and brucipain in Trypanosoma brucei rhodesiense and Trypanosoma brucei brucei, respectively. Three potent and selective dipeptidyl cathepsin L inhibitors have been investigated for their trypanocidal activities in vitro using culture-adapted bloodstream forms of T. b. brucei. Compared with general cysteine proteinase inhibitors used previously by ourselves and others, the present inhibitors had improved selectivity indices and, importantly, anti-trypanosomal activities comparable with those of commercial anti-sleeping sickness drugs. Using purified recombinant rhodesain, potent k(inact)/Ki values of up to 2.3x10(6) M(-1) s(-1) were recorded with the inhibitors. Also, all inhibitors blocked proteinolysis in the lysosome consistent with the inhibition of rhodesain/brucipain. In conclusion, the data support the potential of cathepsin L inhibitors for rational anti-trypanosomal drug development.
authors.affiliation: Abteilung Parasitologie, Hygiene-Institut der Ruprecht-Karls-Universität, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Njinkeng Joseph
authors.initials: NJ
authors.lastname: Nkemgu
authors.forename: Rachel
authors.initials: R
authors.lastname: Grande
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hansell
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.forename: Conor R
authors.initials: CR
authors.lastname: Caffrey
authors.forename: Dietmar
authors.initials: D
authors.lastname: Steverding
mesh_terms: D000818:Animals; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D014168:Transferrin / Q000378:metabolism; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development
chemical_list: D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D014168:Transferrin; D014344:Trypanocidal Agents; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi; C446033:rhodesain; C534281:CTSL protein, human; D056668:Cathepsin L