Dual-pharmacophore artezomibs hijack the Plasmodium ubiquitin-proteasome system to kill malaria parasites while overcoming drug resistance

Cell Chem Biol. 2023 May 18;30(5):457-469.e11. doi: 10.1016/j.chembiol.2023.04.006. Epub 2023 May 5.

Abstract

Artemisinins (ART) are critical anti-malarials and despite their use in combination therapy, ART-resistant Plasmodium falciparum is spreading globally. To counter ART resistance, we designed artezomibs (ATZs), molecules that link an ART with a proteasome inhibitor (PI) via a non-labile amide bond and hijack parasite's own ubiquitin-proteasome system to create novel anti-malarials in situ. Upon activation of the ART moiety, ATZs covalently attach to and damage multiple parasite proteins, marking them for proteasomal degradation. When damaged proteins enter the proteasome, their attached PIs inhibit protease function, potentiating the parasiticidal action of ART and overcoming ART resistance. Binding of the PI moiety to the proteasome active site is enhanced by distal interactions of the extended attached peptides, providing a mechanism to overcome PI resistance. ATZs have an extra mode of action beyond that of each component, thereby overcoming resistance to both components, while avoiding transient monotherapy seen when individual agents have disparate pharmacokinetic profiles.

Keywords: artemisinin; artemisinin resistance; dual-resistance; hybrid; in vivo efficacy; malaria; mouse models of malaria infection; proteasome inhibitor; recrudescence.

Publication types

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

MeSH terms

  • Animals
  • Antimalarials* / chemistry
  • Artemisinins* / pharmacology
  • Drug Resistance
  • Parasites* / metabolism
  • Pharmacophore
  • Plasmodium* / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Ubiquitin

Substances

  • Antimalarials
  • Proteasome Endopeptidase Complex
  • Ubiquitin
  • Artemisinins