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

Communications Biology
Sonali SetuaMaria M Mota

Abstract

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 ...Continue Reading

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Citations

Mar 28, 2021·Parasitology International·Ariel PradiptaMasahiro Yamamoto
Mar 30, 2021·Frontiers in Cell and Developmental Biology·Andreas ZimmermannMahmoud Abdellatif

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Methods Mentioned

BETA
X-ray
flow cytometry
dissection
PCR
transfection

Software Mentioned

GROMACS
MicroCal ITC - origin
Image Lab
ZINC
GraphPad Prism

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