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.
Atg8 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.
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health , 615 North Wolfe Street, Baltimore, Maryland 21205 ( United States ).
Adelaide U P
AU
Hain
David
D
Bartee
Natalie G
NG
Sanders
Alexia S
AS
Miller
David J
DJ
Sullivan
Jelena
J
Levitskaya
Caren Freel
CF
Meyers
Jürgen
J
Bosch
D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D001769:Blood; D062126:Databases, Chemical; D008018:Life Cycle Stages; D008099:Liver / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
D000962:Antimalarials; D015800:Protozoan Proteins; D011725:Pyridines; D013844:Thiazoles