Validation of Babesia proteasome as a drug target

Int J Parasitol Drugs Drug Resist. 2018 Dec;8(3):394-402. doi: 10.1016/j.ijpddr.2018.08.001. Epub 2018 Aug 7.


Babesiosis is a tick-transmitted zoonosis caused by apicomplexan parasites of the genus Babesia. Treatment of this emerging malaria-related disease has relied on antimalarial drugs and antibiotics. The proteasome of Plasmodium, the causative agent of malaria, has recently been validated as a target for anti-malarial drug development and therefore, in this study, we investigated the effect of epoxyketone (carfilzomib, ONX-0914 and epoxomicin) and boronic acid (bortezomib and ixazomib) proteasome inhibitors on the growth and survival of Babesia. Testing the compounds against Babesia divergens ex vivo revealed suppressive effects on parasite growth with activity that was higher than the cytotoxic effects on a non-transformed mouse macrophage cell line. Furthermore, we showed that the most-effective compound, carfilzomib, significantly reduces parasite multiplication in a Babesia microti infected mouse model without noticeable adverse effects. In addition, treatment with carfilzomib lead to an ex vivo and in vivo decrease in proteasome activity and accumulation of polyubiquitinated proteins compared to untreated control. Overall, our results demonstrate that the Babesia proteasome is a valid target for drug development and warrants the design of potent and selective B. divergens proteasome inhibitors for the treatment of babesiosis.

Keywords: Babesia; Carfilzomib; Cytotoxicity; Epoxyketone; Proteasome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Animals
  • Babesia / drug effects*
  • Babesia / genetics
  • Babesia / growth & development
  • Babesia microti / drug effects*
  • Babesia microti / genetics
  • Babesia microti / growth & development
  • Babesiosis / drug therapy
  • Boronic Acids / pharmacology
  • Cell Line
  • Disease Models, Animal
  • Drug Delivery Systems*
  • Female
  • Macrophages / drug effects
  • Macrophages / parasitology
  • Mice
  • Oligopeptides / pharmacology
  • Proteasome Endopeptidase Complex / drug effects
  • Proteasome Inhibitors / administration & dosage
  • Proteasome Inhibitors / adverse effects
  • Proteasome Inhibitors / pharmacology*
  • Proteasome Inhibitors / therapeutic use*
  • Proteome / drug effects*
  • Proteome / genetics


  • Boronic Acids
  • Oligopeptides
  • Proteasome Inhibitors
  • Proteome
  • carfilzomib
  • Proteasome Endopeptidase Complex
  • epoxomicin