Disrupting Plasmodium UIS3-host LC3 interaction with a small molecule causes parasite elimination from host cells

Commun Biol. 2020 Nov 19;3(1):688. doi: 10.1038/s42003-020-01422-1.


The malaria parasite Plasmodium obligatorily infects and replicates inside hepatocytes surrounded by a parasitophorous vacuole membrane (PVM), which is decorated by the host-cell derived autophagy protein LC3. We have previously shown that the parasite-derived, PVM-resident protein UIS3 sequesters LC3 to avoid parasite elimination by autophagy from hepatocytes. Here we show that a small molecule capable of disrupting this interaction triggers parasite elimination in a host cell autophagy-dependent manner. Molecular docking analysis of more than 20 million compounds combined with a phenotypic screen identified one molecule, C4 (4-{[4-(4-{5-[3-(trifluoromethyl) phenyl]-1,2,4-oxadiazol-3-yl}benzyl)piperazino]carbonyl}benzonitrile), capable of impairing infection. Using biophysical assays, we established that this impairment is due to the ability of C4 to disrupt UIS3-LC3 interaction, thus inhibiting the parasite's ability to evade the host autophagy response. C4 impacts infection in autophagy-sufficient cells without harming the normal autophagy pathway of the host cell. This study, by revealing the disruption of a critical host-parasite interaction without affecting the host's normal function, uncovers an efficient anti-malarial strategy to prevent this deadly disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / pharmacology*
  • Antimalarials / therapeutic use
  • Autophagy
  • Cell Adhesion
  • Databases, Chemical
  • Humans
  • Malaria / drug therapy
  • Malaria / parasitology
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Plasmodium berghei / physiology*
  • Plasmodium falciparum / physiology*
  • Protein Binding
  • Protein Conformation
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / metabolism*


  • Antimalarials
  • Membrane Proteins
  • Protozoan Proteins
  • UIS3 protein, Plasmodium falciparum