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

• Published in: Communications biology Vol. 3; no. 1; p. 688
• Main Authors: Setua, Sonali, Enguita, Francisco J., Chora, Ângelo Ferreira, Ranga-prasad, Harish, Lahree, Aparajita, Marques, Sofia, Sundaramurthy, Varadharajan, Mota, Maria M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.11.2020
• Subjects: 13/106; 13/109; 13/31; 13/89; 631/154/1435/2417; 631/154/1435/2418; 64/60; 692/699/255/1629; Biomedical and Life Sciences; Life Sciences
• ISSN: 2399-3642; 2399-3642
• 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. Sonali Setua et al. identify a small molecule which is capable of disrupting the interaction between the plasmodium-derived protein UIS3 and the host protein LC3. Disruption of this interaction by this small molecule triggers parasite elimination from host cells in an autophagy-dependent manner, without affecting the cells’ normal autophagy pathway.