Malaria is one of the most widespread infectious diseases, causing approximately 250 million clinical cases and claiming nearly a million lives each year. Although current artemisinin combination therapies (ACT) have been highly effective against Plasmodium parasites, signs of resistance have already emerged.1 Hence, there is an urgent need for drugs with new modes of action to combat this threat. Apical membrane antigen 1 (AMA1) is an essential component of the moving junction complex used by Plasmodium falciparum to invade human red blood cells.2 AMA1 has a conserved hydrophobic cleft that is the site of key interactions with the RON protein complex.2 Monoclonal antibodies and peptides that target this site on AMA1 inhibit erythrocyte invasion by merozoites, but usually in a strain-specific manner as numerous polymorphic residues are clustered at one end of the groove.
Our goal is to design small molecule inhibitors of AMA1 that have broad strain specificity and we are pursuing this goal using a fragment-based approach.3 In our screening campaign, we have identified 57 fragments that bind to the hydrophobic groove which corresponds to a hit rate of 5%. Chemical modifications of these hits based on the structure-activity-relationships (SARs) of the analogues are currently underway to improve their binding affinities.