Disrupting malaria parasite AMA1–RON2 interaction with a small molecule prevents erythrocyte invasion

• Published in: Nature communications Vol. 4; no. 1; pp. 2261 - 9
• Main Authors: Srinivasan, Prakash, Yasgar, Adam, Luci, Diane K., Beatty, Wandy L., Hu, Xin, Andersen, John, Narum, David L., Moch, J. Kathleen, Sun, Hongmao, Haynes, J. David, Maloney, David J., Jadhav, Ajit, Simeonov, Anton, Miller, Louis H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2013; Nature Publishing Group
• Subjects: 631/92/613; 692/308; 692/699/255/1629; Animals; Antimalarials - analysis; Antimalarials - chemistry; Antimalarials - pharmacology; Artemisinin; Artemisinins - pharmacology; Binding; Chemotherapy; Disruption; Electron microscopy; Erythrocytes; Erythrocytes - drug effects; Erythrocytes - parasitology; Erythrocytes - ultrastructure; Humanities and Social Sciences; Humans; Inhibitors; Inhibitory Concentration 50; Malaria; Malaria - parasitology; Merozoites - drug effects; Merozoites - ultrastructure; multidisciplinary; Parasites; Parasites - drug effects; Parasites - metabolism; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - metabolism; Protein Binding - drug effects; Protein Kinase Inhibitors - pharmacology; Protozoan Proteins - metabolism; Science; Small Molecule Libraries - analysis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Vector-borne diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms3261

Plasmodium falciparum resistance to artemisinin derivatives, the first-line antimalarial drug, drives the search for new classes of chemotherapeutic agents. Current discovery is primarily directed against the intracellular forms of the parasite. However, late schizont-infected red blood cells (RBCs) may still rupture and cause disease by sequestration; consequently targeting invasion may reduce disease severity. Merozoite invasion of RBCs requires interaction between two parasite proteins AMA1 and RON2. Here we identify the first inhibitor of this interaction that also blocks merozoite invasion in genetically distinct parasites by screening a library of over 21,000 compounds. We demonstrate that this inhibition is mediated by the small molecule binding to AMA1 and blocking the formation of AMA1–RON complex. Electron microscopy confirms that the inhibitor prevents junction formation, a critical step in invasion that results from AMA1–RON2 binding. This study uncovers a strategy that will allow for highly effective combination therapies alongside existing antimalarial drugs. Invasion of host erythrocytes is an essential step in the life cycle of P. falciparum. Srinivasan et al. demonstrate that small-molecule inhibitors can block the entry of the parasite into erythrocytes, highlighting the potential of invasion inhibitors as antimalarials.