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

摘要

a Schematic representation of the different steps involved in VLS using ZINC database for P. falciparum with the number of the compounds identified in each phase. b Schematic representation of the experimental steps involved in PHS of selected compounds against P. berghei or PfUIS3@Pb infection in Huh7 cells. c–e Measurement of the antimalarial effect of the selected compounds in P. berghei (c) and PfUIS3@Pb (d and e) infected Huh7 cells using flow cytometry. For c–e, cells were infected 2 h after compound addition and analysed 24 h post-infection. The solvent of the compounds, DMSO (0.001%), was used as the negative control, and Primaquine (10 µM) was used as the positive control. Here, box-plots (10–90 percentile) represent the number of exo-erythrocytic forms, EEFs, as quantified by the number of infected cells. The blue lines (means ± SEM) represent cell confluency. C4 was identified as the most effective compound in case of both P. berghei and PfUIS3@Pb infection. n = 3 independent experiments. P values were calculated using one-way ANOVA with Tukey test, *P < 0.1, **P < 0.01, ***P < 0.001, ****P < 0.0001. f, g Ribbon and solvent accessible surface representation of the homology model of PbUIS3 (f) and the crystal structure of PfUIS3 (PDB code: 2VWA) (g) soluble domains (in grey) in complex with docked compound C4 (in blue). PbUIS3 homology model was built using the crystal structure of PfUIS3 as reference model. Chemical structure of compound C4 and amino acid residues involved in the interaction of UIS3 proteins with LC3 in P. berghei and P. falciparum are depicted in sticks. h Chemical structure and properties of C4.