Nicotinamide inhibits the lysosomal cathepsin b-like protease and kills African trypanosomes

J Biol Chem. 2013 Apr 12;288(15):10548-57. doi: 10.1074/jbc.M112.449207. Epub 2013 Feb 26.

Abstract

Nicotinamide, a soluble compound of the vitamin B3 group, has antimicrobial activity against several microorganisms ranging from viruses to parasite protozoans. However, the mode of action of this antimicrobial activity is unknown. Here, we investigate the trypanocidal activity of nicotinamide on Trypanosoma brucei, the causative agent of African trypanosomiasis. Incubation of trypanosomes with nicotinamide causes deleterious defects in endocytic traffic, disruption of the lysosome, failure of cytokinesis, and, ultimately, cell death. At the same concentrations there was no effect on a cultured mammalian cell line. The effects on endocytosis and vesicle traffic were visible within 3 h and can be attributed to inhibition of lysosomal cathepsin b-like protease activity. The inhibitory effect of nicotinamide was confirmed by a direct activity assay of recombinant cathepsin b-like protein. Taken together, these data demonstrate that inhibition of the lysosomal protease cathepsin b-like blocks endocytosis, causing cell death. In addition, these results demonstrate for the first time the inhibitory effect of nicotinamide on a protease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cathepsin B / antagonists & inhibitors*
  • Cathepsin B / metabolism
  • Endocytosis / drug effects
  • Human Umbilical Vein Endothelial Cells / parasitology
  • Humans
  • Lysosomes / enzymology
  • Niacinamide / pharmacology*
  • Protein Transport / drug effects
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / metabolism
  • Trypanosoma brucei brucei / cytology
  • Trypanosoma brucei brucei / enzymology*
  • Trypanosomiasis, African / drug therapy
  • Trypanosomiasis, African / enzymology
  • Vitamin B Complex / pharmacology*

Substances

  • Protozoan Proteins
  • Vitamin B Complex
  • Niacinamide
  • Cathepsin B