Identification of an Atg8-Atg3 Protein鈥揚rotein Interaction Inhibitor from the Medicines for Malaria Venture Malaria Box Active in Blood and Liver Stage Plasmodium falciparum Parasites

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• 作者：Adelaide U.P. Hain ; David Bartee ; Natalie G. Sanders ; Alexia S. Miller ; David J. Sullivan ; Jelena Levitskaya ; Caren Freel Meyers ; J眉rgen Bosch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 12, 2014
• 年：2014
• 卷：57
• 期：11
• 页码：4521-4531
• 全文大小：674K
• 年卷期：v.57,no.11(June 12, 2014)
• ISSN：1520-4804

文摘

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鈥檚 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鈥損rotein 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.