MALARIA: Disrupting malaria parasite AMA1–RON2interaction 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
• & Louis H. Miller

• Affiliations
• Contributions
• Corresponding author

Nature Communications

 

4,

 

Article number:

 

2261

 

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 AMA1and 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.