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Identification of an Atg8-Atg3 Protein–Protein Interaction Inhibitor from the Medicines for Malaria Venture Malaria Box Active in Blood and Liver Stage Plasmodium falciparum Parasites
journal contribution
posted on 2015-12-17, 02:36 authored by Adelaide
U.P. Hain, David Bartee, Natalie G. Sanders, Alexia
S. Miller, David J. Sullivan, Jelena Levitskaya, Caren Freel Meyers, Jürgen BoschAtg8 is a ubiquitin-like
autophagy protein in eukaryotes that is
covalently attached (lipidated) to the elongating autophagosomal membrane.
Autophagy is increasingly appreciated as a target in diverse diseases
from cancer to eukaryotic parasitic infections. Some of the autophagy
machinery is conserved in the malaria parasite, Plasmodium. Although Atg8’s function in the parasite is not well understood,
it is essential for Plasmodium growth and survival
and partially localizes to the apicoplast, an indispensable organelle
in apicomplexans. Here, we describe the identification of inhibitors
from the Malaria Medicine Venture Malaria Box against the interaction
of PfAtg8 with its E2-conjugating enzyme, PfAtg3, by surface plasmon resonance. Inhibition of this
protein–protein interaction prevents PfAtg8
lipidation with phosphatidylethanolamine. These small molecule inhibitors
share a common scaffold and have activity against both blood and liver
stages of infection by Plasmodium falciparum. We
have derivatized this scaffold into a functional platform for further
optimization.
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PfAtg 8autophagy machineryPlasmodium falciparumscaffoldidentificationelongating autophagosomal membraneinteractionmolecule inhibitors sharemalaria parasiteliver stagesPfAtg 8 lipidationinfectionPlasmodium growthsurface plasmon resonanceMalaria Venture Malaria BoxproteinMalaria Medicine Venture Malaria BoxLiver Stage Plasmodium falciparum ParasitesAtg 8