Research Summary

Systematic development of novel therapeutics against malaria

The goal of my research is to systematically develop novel high affinity D-protein based inhibitors of Plasmodium falciparum AMA1-RON2 protein-protein interaction using ‘mirror image phage display’. D-proteins have advantageous properties: they are resistant to proteolytic degradation, amenable to chemical manufacture, and are known to be non-immunogenic. Therefore, a properly engineered D-protein inhibitor would be superior to a conventional natural peptide/protein (consisting of all L-amino acids and glycine) as a therapeutic. Inhibiting the interaction between AMA1 and RON2 proteins was chosen for the following reasons. Malaria transmission can be prevented by inhibiting the invasion of uninfected erythrocytes by merozoites. Studies suggest that formation of a moving junction between the merozoite and an erythrocyte that involves two key proteins, apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2), is critical for merozoite invasion. The AMA1 at the merozoite surface binds to the extracellular domain of RON-2, located outside the membrane of erythrocyte, for effective junction formation. Interestingly, both the proteins involved in moving junction formation are parasite proteins. Therefore, turning off the interaction between AMA1 and RON2 by a potent, stable D-protein inhibitor would be an ideal strategy to prevent the junction formation, and thereby prevent invasion by merozoites.

Figure Legend: Mirror image protein phage display: development of novel D-protein inhibitor of P. falciparum AMA1-RON2 interaction