Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice

Angew Chem Int Ed Engl. 2021 Apr 19;60(17):9279-9283. doi: 10.1002/anie.202015845. Epub 2021 Mar 11.

Abstract

Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages-erythrocytic, gametocyte, liver, and gamete activation stages-indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission-blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time-dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin-sensitive and artemisinin-resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum-infected mice.

Keywords: inhibitors; malaria; proteasome; selectivity; therapeutics.

Publication types

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

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Drug Development*
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / metabolism
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / chemical synthesis
  • Proteasome Inhibitors / chemistry
  • Proteasome Inhibitors / pharmacology*

Substances

  • Antimalarials
  • Proteasome Inhibitors
  • Proteasome Endopeptidase Complex