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

Prakash Srinivasan (), Adam Yasgar, Diane K. Luci, Wandy L. Beatty, Xin Hu, John Andersen, David L. Narum, J. Kathleen Moch, Hongmao Sun, J. David Haynes, David J. Maloney, Ajit Jadhav, Anton Simeonov and Louis H. Miller
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Prakash Srinivasan: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Adam Yasgar: National Center for Advancing Translational Sciences, National Institutes of Health
Diane K. Luci: National Center for Advancing Translational Sciences, National Institutes of Health
Wandy L. Beatty: Washington University School of Medicine
Xin Hu: National Center for Advancing Translational Sciences, National Institutes of Health
John Andersen: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
David L. Narum: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
J. Kathleen Moch: Walter Reed Army Institute of Research
Hongmao Sun: National Center for Advancing Translational Sciences, National Institutes of Health
J. David Haynes: Walter Reed Army Institute of Research
David J. Maloney: National Center for Advancing Translational Sciences, National Institutes of Health
Ajit Jadhav: National Center for Advancing Translational Sciences, National Institutes of Health
Anton Simeonov: National Center for Advancing Translational Sciences, National Institutes of Health
Louis H. Miller: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Nature Communications, 2013, vol. 4, issue 1, 1-9

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms3261

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