Trypanosoma brucei: Inhibition of cathepsin L is sufficient to kill bloodstream forms

Mol Biochem Parasitol. 2020 Jan:235:111246. doi: 10.1016/j.molbiopara.2019.111246. Epub 2019 Nov 16.

Abstract

The lysosomal cysteine protease activity of Trypanosoma brucei comprises a cathepsin B enzyme (TbCATB) and a cathepsin L enzyme (TbCATL). Inhibition of the cysteine protease activity is lethal to bloodstream-form trypanosomes but it was not entirely clear which of the two enzymes are essential for survival of the parasites. Here we show that the vinyl sulfone compound LU-102 selectively inhibits TbCATL without affecting TbCATB and the proteasomal trypsin-like activity within trypanosomes. Therefore, the trypanocidal activity displayed by LU-102 can be attributed solely to the inhibition of TbCATL demonstrating that this enzyme is essential to the survival of T. brucei.

Keywords: African trypanosomiasis; Cysteine protease; Protease inhibitor; Trypanosoma brucei.

MeSH terms

  • Animals
  • Cathepsin B* / antagonists & inhibitors
  • Cathepsin B* / metabolism
  • Cathepsin L* / antagonists & inhibitors
  • Cathepsin L* / metabolism
  • Cysteine Proteinase Inhibitors / metabolism
  • Proteasome Endopeptidase Complex / drug effects
  • Proteasome Endopeptidase Complex / metabolism
  • Protozoan Proteins / antagonists & inhibitors
  • Sulfones / pharmacology*
  • Sulfones / therapeutic use
  • Trypanosoma brucei brucei* / drug effects
  • Trypanosoma brucei brucei* / enzymology
  • Trypanosoma brucei brucei* / growth & development
  • Trypanosomiasis, African / drug therapy
  • Trypanosomiasis, African / parasitology

Substances

  • Cysteine Proteinase Inhibitors
  • Protozoan Proteins
  • Sulfones
  • divinyl sulfone
  • Cathepsin B
  • Cathepsin L
  • Proteasome Endopeptidase Complex