Improved trypanocidal activities of cathepsin L inhibitors

Int J Antimicrob Agents. 2003 Aug;22(2):155-9. doi: 10.1016/s0924-8579(03)00096-7.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cathepsin L
  • Cathepsins / antagonists & inhibitors*
  • Cysteine Endopeptidases / metabolism
  • Cysteine Proteinase Inhibitors / pharmacology*
  • HL-60 Cells
  • Humans
  • In Vitro Techniques
  • Kinetics
  • Protozoan Proteins / antagonists & inhibitors
  • Transferrin / metabolism
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma brucei brucei / drug effects*
  • Trypanosoma brucei brucei / enzymology
  • Trypanosoma brucei brucei / growth & development
  • Trypanosoma brucei rhodesiense / drug effects*
  • Trypanosoma brucei rhodesiense / enzymology
  • Trypanosoma brucei rhodesiense / growth & development


  • Cysteine Proteinase Inhibitors
  • Protozoan Proteins
  • Transferrin
  • Trypanocidal Agents
  • Cathepsins
  • Cysteine Endopeptidases
  • cruzain, Trypanosoma cruzi
  • rhodesain
  • CTSL protein, human
  • Cathepsin L