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

Nature Communications; 4,
Article number:: 2261; doi:10.1038/ncomms3261

Received: 21 December 2012
Accepted: 05 July 2013
Published: 02 August 2013

Abstract

Plasmodium falciparum resistance to 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 and . 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 and blocking the formation of –RON complex. Electron microscopy confirms that the inhibitor prevents junction formation, a critical step in invasion that results from – binding. This study uncovers a strategy that will allow for highly effective combination therapies alongside existing antimalarial drugs.